Dosage regimen for anti-CDH6 antibody-drug conjugates

Abstract

The present disclosure relates to the field of pharmaceutical formulations, dosage regimens, and administration of antibody-drug conjugates (ADCs). More specifically, the ADC consists of an anticadherin-6 (CDH6) antibody linked via a linker to an anti-cancer agent, such as a topoisomerase I inhibitor.

Description

[0001] Statement regarding sequence listing This application contains a sequence listing submitted electronically in XML format and which is hereby incorporated by reference in its entirety. The XML copy created on May 23, 2023 is named 098065-0328.xml and is 118kb in size. Technical Field

[0002] The present disclosure relates to the field of pharmaceutical formulations, dosage regimens and administration of antibody-drug conjugates (ADCs). More specifically, the ADCs consist of an anti-cadherin-6 (CDH6) antibody linked via a linker to a topoisomerase I inhibitor, such as a derivative of exatecan. Background Art

[0003] Cadherin is a glycoprotein present on the cell membrane surface, and is combined as a cell-cell adhesion molecule by the calcium ion dependence of its N-terminal extracellular domain, or functions as a signal molecule responsible for cell-cell interaction. Classical cadherin is in the cadherin superfamily and is a single transmembrane protein consisting of five extracellular domains (EC domain), a transmembrane region and an intracellular domain. According to the homology of its amino acid sequence, classical cadherin is classified into type I family (it is represented by E-cadherin and N-cadherin) and type II family.

[0004] Cadherin-6 (CDH6) is a single transmembrane protein consisting of 790 amino acids, which is classified as the type II cadherin family, and the protein has an N-terminal extracellular and C-terminal intracellular domains. Human CDH6 gene was first cloned in 1995 (Non-patent Document 1), and its sequence can refer to, for example, accession numbers NM_004932 and NP_004923 (NCBI).

[0005] CDH6 is specifically expressed in the brain or kidney during development, and has been reported to play an important role in the formation of circuits in the central nervous system (Non-Patent Documents 2 and 3) and the development of nephrons in the kidney (Non-Patent Documents 4 and 5). The expression of CDH6 in normal tissues of adults is limited to renal tubules, bile duct epithelial cells, etc. in the kidney.

[0006] At the same time, it is known that in some types of human adult cancers, CDH6 is specifically overexpressed at the tumor site. Regarding human renal cell carcinoma, in particular, renal clear cell carcinoma, the correlation between CDH6 expression and poor prognosis and its applicability as a tumor marker have been reported (non-patent literature 6 and 7). Regarding human ovarian cancer, the high expression of CDH6 has also been reported (non-patent literature 8). It has also been reported that CDH6 is related to the epithelial-mesenchymal transition of human thyroid cancer (non-patent literature 9). In addition, it has been reported that CDH6 is also expressed in human cholangiocarcinoma and human small cell lung cancer (non-patent literature 12 and 13).

[0007] Cancer ranks high among the causes of death. Although the number of cancer patients is expected to increase with the aging of the population, the need for treatment has not yet been fully met. The problem with conventional chemotherapy drugs is that due to their low selectivity, these chemotherapy drugs are toxic not only to tumor cells, but also to normal cells, and thus have adverse reactions; and chemotherapy drugs cannot be administered in sufficient amounts, and therefore cannot fully produce their effects. Therefore, in recent years, more highly selective molecular target drugs or antibody drugs have been developed, which target molecules that display mutations or high expression characteristics in cancer cells, or target specific molecules related to cell malignant transformation.

[0008] Antibodies are highly stable in the blood and specifically bind to their target antigens. For these reasons, a decline in adverse reactions is expected, and a large number of antibody drugs have been developed for molecules highly expressed on the surface of cancer cells. One of the technologies that rely on the antigen-specific binding ability of antibodies is the use of antibody-drug conjugates (ADCs). ADC is a conjugate in which the antigen expressed on the surface of cancer cells and the antibody that can be internalized into the cell by the combination is conjugated to a drug with cytotoxic activity. ADC can effectively deliver drugs to cancer cells, and therefore it can be expected that cancer cells will be killed by accumulating drugs in cancer cells (non-patent literature 10 and patent literature 1 and 2). About ADC, for example, Adcetris (TM) (brentuximab vedotin) comprising an anti-CD30 monoclonal antibody conjugated to monomethyl auristatin E has been approved as a therapeutic drug for Hodgkin's lymphoma and anaplastic large cell lymphoma. Likewise, Kadcyla(TM) (trastuzumab emtansine), which comprises an anti-HER2 monoclonal antibody conjugated to emtansine, is used to treat HER2-positive progressive or recurrent breast cancer.

[0009] The characteristics of target antigens suitable for ADCs as anti-tumor drugs are: the antigen is specifically highly expressed on the surface of cancer cells, but lowly expressed or not expressed in normal cells; the antigen can be internalized into cells; the antigen is not secreted from the cell surface, etc. The internalization ability of an antibody depends on the properties of both the target antigen and the antibody. It is difficult to predict an antigen binding site suitable for internalization from the molecular structure of the target, or to predict an antibody with high internalization ability from the binding strength, physical properties, etc. of the antibody. Therefore, an important challenge in developing ADCs with high efficacy is to obtain antibodies with high internalization ability against target antigens (Non-patent Document 11).

[0010] ADCs comprising DM4 conjugated to an anti-CDH6 antibody that specifically binds to the EC domain 5 (EC5) of CDH6 are referred to as CDH6-targeted ADCs (Patent Document 3, Non-Patent Documents 14 and 15). ADCs comprising exotecan derivatives conjugated to an anti-CDH6 antibody that specifically binds to the EC domain 3 (EC3) of CDH6 are known (Patent Documents 4 and 5).

[0011] Reference List Patent Literature Patent Document 1: WO2014 / 057687 Patent Document 2: US2016 / 0297890 Patent Document 3: WO2016 / 024195 Patent Document 4: WO2018 / 212136 Patent Document 5: WO2023 / 042097 Non-patent literature Non-patent document 1: Shimoyama Y et al., Cancer Research, 2206-2211, 55, May 15, 1995 Non-patent document 2: Inoue T et al., Developmental Biology, 183-194, 1997 Non-patent document 3: Osterhout JA et al., Neuron, 632-639, 71, August 25, 2011 Non-patent document 4: Cho EA et al., Development, 803-812, 125, 1998 Non-patent document 5: Mah SP et al., Developmental Biology, 38-53, 223, 2000 Non-patent document 6: Paul R et al., Cancer Research, 2741-2748, July 1, 57, 1997 Non-patent document 7: Shimazui T et al., Cancer, 963-968, 101(5), September 1, 2004 Non-patent document 8: Koebel M et al., PLoS Medicine, 1749-1760, 5(12), e232, December 2008 Non-patent document 9: Gugnoni M et al., Oncogene, 667-677, 36, 2017 Non-patent literature 10: Polakis P., Pharmacological Reviews, 3-19, 68, 2016 Non-patent document 11: Peters C et al., Bioscience Reports, 1-20, 35, 2015 Non-patent document 12: Goeppert B et al., Epigenetics, 780-790, 11(11), 2016 Non-patent document 13: Yokoi S et al., American Journal of Pathology, 207-216, 161, 1, 2002 Non-patent document 14: Bialucha et al., Cancer Discovery, 1030-1045, 7, 9.2017.

[0012] Non-patent document 15: et al., Oncology Research and Treatment, 547-556, 44, 10, 2021. Summary of the invention

[0013] The present disclosure provides methods for treating cancer in a subject in need thereof, comprising administering a specific anti-CDH6 antibody-drug conjugate to the subject according to a specific dosing regimen, and a pharmaceutical composition for treating cancer according to the dosing regimen. The present disclosure also provides methods for treating renal cell carcinoma or ovarian cancer in a subject in need thereof, comprising administering a specific anti-CDH6 antibody-drug conjugate to the subject, and a pharmaceutical composition for treating renal cell carcinoma or ovarian cancer comprising an anti-CDH6 antibody-drug conjugate.

[0014] The present disclosure includes the following aspects: [1] An anti-CDH6 antibody-drug conjugate for use in treating or preventing cancer, the antibody-drug conjugate comprising an anti-CDH6 antibody and an anti-tumor compound connected by a linker, wherein the linker and the anti-tumor compound are represented by the following formula: -(Succinimide-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) wherein -(Succinimide-3-yl-N)- has a structure represented by the following formula: It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: The nitrogen atom of the amino group at position 1 is a connection position, wherein the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

[0015] [2] The antibody-drug conjugate according to [1], wherein the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 63.

[0016] [3] The antibody-drug conjugate according to [1] or [2], which has a structure represented by the following formula: wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

[0017] [4] The antibody-drug conjugate according to any one of [1] to [3], wherein the antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 in SEQ ID NO:69 and a light chain comprising the amino acid sequence of positions 21 to 233 in SEQ ID NO:61.

[0018] [5] The antibody-drug conjugate according to any one of [1] to [4], wherein the heavy chain or light chain has undergone one or two or more modifications selected from the following: N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus.

[0019] [6] The antibody-drug conjugate according to any one of [1] to [5], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0020] [7] The antibody-drug conjugate according to any one of [1] to [6], wherein the average number of units of the anti-tumor compound conjugated per antibody is in the range of 2 to 8.

[0021] [8] The antibody-drug conjugate according to any one of [1] to [7], wherein the average number of units of the anti-tumor compound conjugated per antibody is 7 to 8.

[0022] [9] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

[0023]

[10] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

[0024]

[11] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

[0025]

[12] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 8.0 mg / kg is administered to a subject suffering from cancer.

[0026]

[13] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 6.4 mg / kg is administered to a subject suffering from cancer.

[0027]

[14] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 8.0 mg / kg is administered to a subject suffering from cancer.

[0028]

[15] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 6.4 mg / kg is administered to a subject suffering from cancer.

[0029]

[16] The antibody-drug conjugate of any one of [1] to [8], wherein a dose of about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg or about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0030]

[17] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0031]

[18] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0032]

[19] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of about 5.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0033]

[20] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of about 5.6 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0034]

[21] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0035]

[22] The antibody-drug conjugate according to any one of [1] to [8], wherein a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0036]

[23] The antibody-drug conjugate of any one of [1] to [8], wherein 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, or 6.4 mg / kg of the antibody-drug conjugate.

[0037]

[24] The antibody-drug conjugate according to any one of [1] to

[23] , wherein the antibody-drug conjugate is administered by intravenous administration.

[0038]

[25] The antibody-drug conjugate according to any one of [1] to

[24] , wherein the antibody-drug conjugate is administered once every 3 weeks.

[0039]

[26] The antibody-drug conjugate of any one of [1] to

[25] , wherein the cancer is selected from renal cell carcinoma, clear cell renal carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, clear cell carcinoma of the ovary, endometrioid carcinoma of the ovary, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, nasopharyngeal carcinoma, prostate cancer or cancer associated with von Schiele-Lin disease.

[0040]

[27] The antibody-drug conjugate according to

[26] , wherein the cancer is renal cell carcinoma, clear cell renal carcinoma or papillary renal cell carcinoma.

[0041]

[28] The antibody-drug conjugate according to

[26] , wherein the cancer is ovarian cancer.

[0042]

[29] The antibody-drug conjugate of

[28] , wherein the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

[0043]

[30] The antibody-drug conjugate according to any one of [1] to

[29] , wherein the cancer is metastatic.

[0044]

[31] The antibody-drug conjugate according to any one of [1] to

[30] , wherein the cancer is resistant or refractory.

[0045]

[32] The antibody-drug conjugate according to

[31] , wherein the resistance or refractory nature is resistance or refractory nature acquired by cancer due to treatment with an anticancer drug.

[0046]

[33] The antibody-drug conjugate according to

[32] , wherein the anticancer drug is a platinum-based chemotherapy drug, a chemotherapy drug, a PARP inhibitor, an immune checkpoint inhibitor, an angiogenesis inhibitor or a VEGFR-TKI.

[0047]

[34] The antibody-drug conjugate according to any one of [1] to

[33] , wherein the subject has a history of treatment with one or two or more anti-cancer drugs selected from platinum-based chemotherapy drugs, chemotherapeutic drugs, PARP inhibitors, immune checkpoint inhibitors, angiogenesis inhibitors and VEGFR-TKIs.

[0048]

[35] The antibody-drug conjugate according to

[32] , wherein the anticancer drug is a platinum-based chemotherapy drug.

[0049]

[36] The antibody-drug conjugate according to

[35] , wherein the platinum-based chemotherapy drug comprises a platinum-based drug and a taxane.

[0050]

[37] The antibody-drug conjugate according to any one of [1] to

[36] , wherein the cancer is a cancer expressing CDH6.

[0051]

[38] The antibody-drug conjugate according to

[37] , wherein the cancer expressing CDH6 is a cancer overexpressing CDH6.

[0052]

[39] The antibody-drug conjugate according to any one of [1] to

[38] , wherein the cancer is an inoperable or recurrent cancer.

[0053]

[40] The antibody-drug conjugate according to any one of [1] to

[39] , wherein the subject exhibits recurrence of cancer prior to administration of the antibody-drug conjugate.

[0054]

[41] The antibody-drug conjugate of

[40] , wherein recurrence of the cancer occurs within about six months or less of completing a chemotherapy regimen comprising a platinum-based drug.

[0055]

[42] The antibody-drug conjugate of

[40] , wherein recurrence of the cancer occurs within about six months or less of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0056]

[43] The antibody-drug conjugate of

[40] , wherein recurrence of the cancer occurs within or after about six months of completion of a chemotherapy regimen comprising a platinum-based drug.

[0057]

[44] The antibody-drug conjugate of

[40] , wherein recurrence of the cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0058]

[45] The antibody-drug conjugate according to any one of [1] to

[44] , wherein the objective response rate of the subject is at least about 20%.

[0059]

[46] The antibody-drug conjugate according to any one of [1] to

[44] , wherein the objective response rate of the subject is at least about 30%.

[0060]

[47] The antibody-drug conjugate according to any one of [1] to

[46] , wherein the progression free survival of the subject after administration of the antibody-drug conjugate is at least 5 months.

[0061]

[48] ​​The antibody-drug conjugate according to any one of [1] to

[46] , wherein the progression-free survival of the subject after administration of the antibody-drug conjugate is at least 5.5 months.

[0062]

[49] The antibody-drug conjugate according to any one of [1] to

[48] , wherein the antibody-drug conjugate is administered as a monotherapy.

[0063]

[50] The antibody-drug conjugate according to any one of [1] to

[48] , wherein the antibody-drug conjugate is administered to a subject together with a second drug.

[0064]

[51] The antibody-drug conjugate according to

[50] , wherein the antibody-drug conjugate is administered before, after or simultaneously with the second drug.

[0065]

[52] The antibody-drug conjugate according to any one of [1] to

[44] , wherein the antibody-drug conjugate is administered as maintenance therapy.

[0066]

[53] The antibody-drug conjugate according to any one of [1] to

[44] , wherein the antibody-drug conjugate is administered as an adjuvant therapy.

[0067]

[54] The antibody-drug conjugate according to any one of [1] to

[44] , wherein the antibody-drug conjugate is administered after surgical resection of the tumor.

[0068]

[55] The antibody-drug conjugate according to any one of [1] to

[44] , wherein the antibody-drug conjugate is administered as a tumor adjuvant therapy.

[0069]

[56] The antibody-drug conjugate according to any one of [1] to

[44] , wherein the antibody-drug conjugate is administered before surgical resection of the tumor.

[0070]

[57] An anti-CDH6 antibody-drug conjugate for use in treating or preventing cancer, wherein the anti-CDH6 antibody-drug conjugate has a structure represented by the following formula: wherein AB represents an anti-CDH6 antibody or a functional fragment of the antibody, n represents the average number of units of a drug-linker structure conjugated to the antibody per antibody, and the antibody is connected to the linker via a thiol group derived from the antibody; and wherein the anti-CDH6 antibody-drug conjugate is a salt thereof or a hydrate of the anti-CDH6 antibody-drug conjugate or the salt, wherein the average number of units of the drug-linker structure conjugated to each antibody is 7 to 8, wherein the antibody comprises: a heavy chain amino acid sequence as shown in SEQ ID NO: 87 or an amino acid sequence derived from the amino acid sequence as shown in SEQ ID NO: 87 in which one or two amino acids are deleted from its carboxyl terminus; and a light chain amino acid sequence as shown in SEQ ID NO: 88, wherein the dosage of the antibody-drug conjugate is in the range of 1.6 mg / kg to 9.6 mg / kg, wherein the antibody-drug conjugate is administered by intravenous administration, wherein the antibody-drug conjugate is administered once every 3 weeks.

[0071]

[58] A pharmaceutical composition comprising the antibody-drug conjugate or a salt thereof according to any one of [1] to

[57] as an active ingredient and a pharmaceutically acceptable formulation component.

[0072]

[59] A method for treating or preventing cancer in a subject, comprising administering to a subject suffering from cancer an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate comprises an anti-CDH6 antibody and an anti-tumor compound connected by a linker, wherein the linker and the anti-tumor compound are represented by the following formula: -(Succinimide-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) wherein -(Succinimide-3-yl-N)- has a structure represented by the following formula: It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: The nitrogen atom of the amino group at position 1 is a connection position, wherein the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

[0073]

[60] The method according to

[59] , wherein the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:63.

[0074]

[61] The method according to

[59] or

[60] , wherein the antibody-drug conjugate has a structure represented by the following formula: wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

[0075]

[62] The method according to any one of

[59] to

[61] , wherein the antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 in SEQ ID NO:69 and a light chain comprising the amino acid sequence of positions 21 to 233 in SEQ ID NO:61.

[0076]

[63] A method according to any one of

[59] to

[62] , wherein the heavy chain or light chain has undergone one or two or more modifications selected from the following: N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus.

[0077]

[64] The method according to any one of

[59] to

[63] , wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0078]

[65] The method according to any one of

[59] to

[64] , wherein the average number of units of the anti-tumor compound conjugated per antibody is in the range of 2 to 8.

[0079]

[66] The method according to any one of

[59] to

[65] , wherein the average number of units of the anti-tumor compound conjugated per antibody is 7 to 8.

[0080]

[67] The method of any one of

[59] to

[66] , wherein a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to the subject suffering from cancer.

[0081]

[68] The method of any one of

[59] to

[66] , wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 9.6 mg / kg is administered to the subject suffering from cancer.

[0082]

[69] The method of any one of

[59] to

[66] , wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 9.6 mg / kg is administered to the subject suffering from cancer.

[0083]

[70] The method of any one of

[59] to

[66] , wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 8.0 mg / kg is administered to the subject suffering from cancer.

[0084]

[71] The method of any one of

[59] to

[66] , wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 6.4 mg / kg is administered to the subject suffering from cancer.

[0085]

[72] The method of any one of

[59] to

[66] , wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 8.0 mg / kg is administered to the subject suffering from cancer.

[0086]

[73] The method of any one of

[59] to

[66] , wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 6.4 mg / kg is administered to the subject suffering from cancer.

[0087]

[74] The method of any one of

[59] to

[66] , wherein a dose of about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg or about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0088]

[75] The method of any one of

[59] to

[66] , wherein a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0089]

[76] The method of any one of

[59] to

[66] , wherein a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0090]

[77] The method of any one of

[59] to

[66] , wherein a dose of about 5.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0091]

[78] The method of any one of

[59] to

[66] , wherein a dose of about 5.6 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0092]

[79] The method of any one of

[59] to

[66] , wherein a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0093]

[80] The method of any one of

[59] to

[66] , wherein a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0094]

[81] The method of any one of

[59] to

[66] , wherein 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, or 6.4 mg / kg of the antibody-drug conjugate.

[0095]

[82] The method according to any one of

[59] to

[81] , wherein the antibody-drug conjugate is administered by intravenous administration.

[0096]

[83] The method according to any one of

[59] to

[82] , wherein the antibody-drug conjugate is administered once every 3 weeks.

[0097]

[84] The method of any one of

[59] to

[83] , wherein the cancer is selected from renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, clear cell carcinoma of the ovary, endometrioid carcinoma of the ovary, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, nasopharyngeal carcinoma, prostate cancer or cancer associated with von Schiele-Lin disease.

[0098]

[85] The method of

[84] , wherein the cancer is renal cell carcinoma, clear cell renal cell carcinoma, or papillary renal cell carcinoma.

[0099]

[86] The method of

[84] , wherein the cancer is ovarian cancer.

[0100]

[87] The method of

[86] , wherein the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

[0101]

[88] The antibody-drug conjugate of any one of

[59] to

[87] , wherein the cancer is metastatic.

[0102]

[89] The method of any one of

[59] to

[88] , wherein the cancer is resistant or refractory.

[0103]

[90] The method according to

[89] , wherein the resistance or refractory nature is resistance or refractory nature acquired by cancer due to treatment with an anticancer drug.

[0104]

[91] The method according to

[90] , wherein the anticancer drug is a platinum-based chemotherapy drug, a chemotherapy drug, a PARP inhibitor, an immune checkpoint inhibitor, an angiogenesis inhibitor or a VEGFR-TKI.

[0105]

[92] The method according to any one of

[59] to

[91] , wherein the subject has a history of treatment with one or two or more anti-cancer drugs selected from platinum-based chemotherapy drugs, chemotherapeutic drugs, PARP inhibitors, immune checkpoint inhibitors, angiogenesis inhibitors and VEGFR-TKIs.

[0106]

[93] The method according to

[90] , wherein the anticancer drug is a platinum-based chemotherapy drug.

[0107]

[94] The method according to

[93] , wherein the platinum-based chemotherapy drug comprises a platinum-based drug and a taxane.

[0108]

[95] The method of any one of

[59] to

[94] , wherein the cancer is a cancer expressing CDH6.

[0109]

[96] The method according to

[95] , wherein the cancer expressing CDH6 is a cancer overexpressing CDH6.

[0110]

[97] The method of any one of

[59] to

[96] , wherein the cancer is an inoperable or recurrent cancer.

[0111]

[98] The method of any one of

[59] to

[97] , wherein the subject exhibits recurrence of cancer prior to administration of the antibody-drug conjugate.

[0112]

[99] The method of

[98] , wherein recurrence of the cancer occurs within about six months or less of completing a chemotherapy regimen comprising a platinum-based drug.

[0113]

[100] The method of

[98] , wherein recurrence of the cancer occurs within about six months or less of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0114]

[101] The method of

[98] , wherein recurrence of the cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug.

[0115]

[102] The method of

[98] , wherein recurrence of the cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0116]

[103] The method of any one of

[59] to

[102] , wherein the subject's objective response rate is at least about 20%.

[0117]

[104] The method of any one of

[59] to

[102] , wherein the subject's objective response rate is at least about 30%.

[0118]

[105] The method according to any one of

[59] to

[104] , wherein the subject's progression-free survival is at least 5 months after administration of the antibody-drug conjugate.

[0119]

[106] The method according to any one of

[59] to

[104] , wherein the subject has a progression-free survival of at least 5.5 months after administration of the antibody-drug conjugate.

[0120]

[107] The method of any one of

[59] to

[106] , wherein the antibody-drug conjugate is administered as a monotherapy.

[0121]

[108] The method according to any one of

[59] to

[106] , wherein the antibody-drug conjugate is administered to the subject together with a second drug.

[0122]

[109] The method according to

[108] , wherein the antibody-drug conjugate is administered before, after or simultaneously with the second drug.

[0123]

[110] The method of any one of

[59] to

[102] , wherein the antibody-drug conjugate is administered as maintenance therapy.

[0124]

[111] The method according to any one of

[59] to

[102] , wherein the antibody-drug conjugate is administered as an adjuvant therapy.

[0125]

[112] The method of any one of

[59] to

[102] , wherein the antibody-drug conjugate is administered after surgical resection of the tumor.

[0126]

[113] The method according to any one of

[59] to

[102] , wherein the antibody-drug conjugate is administered as a tumor adjuvant therapy.

[0127]

[114] The method of any one of

[59] to

[102] , wherein the antibody-drug conjugate is administered prior to surgical resection of the tumor.

[0128]

[115] A method for treating or preventing cancer in a subject, comprising administering to a subject having cancer an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate has a structure represented by the following formula: wherein AB represents an anti-CDH6 antibody or a functional fragment of the antibody, n represents the average number of units of a drug-linker structure conjugated to the antibody per antibody, and the antibody is connected to the linker via a thiol group derived from the antibody; and wherein the anti-CDH6 antibody-drug conjugate is a salt thereof or a hydrate of the anti-CDH6 antibody-drug conjugate or the salt, wherein the average number of units of the drug-linker structure conjugated to each antibody is 7 to 8, wherein the antibody comprises: a heavy chain amino acid sequence as shown in SEQ ID NO: 87 or an amino acid sequence derived from the amino acid sequence as shown in SEQ ID NO: 87 in which one or two amino acids are deleted from its carboxyl terminus; and a light chain amino acid sequence as shown in SEQ ID NO: 88, wherein the dosage of the antibody-drug conjugate is in the range of 1.6 mg / kg to 9.6 mg / kg, wherein the antibody-drug conjugate is administered by intravenous administration, wherein the antibody-drug conjugate is administered once every 3 weeks.

[0129]

[116] The method according to any one of

[59] to

[115] , wherein the antibody-drug conjugate is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable formulation component.

[0130]

[117] Use of an anti-CDH6 antibody-drug conjugate in the preparation of a drug for treating or preventing cancer, wherein the antibody-drug conjugate comprises an anti-CDH6 antibody and an anti-tumor compound connected by a linker, wherein the linker and the anti-tumor compound are represented by the following formula: -(Succinimide-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) wherein -(Succinimide-3-yl-N)- has a structure represented by the following formula: It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: The nitrogen atom of the amino group at position 1 is a connection position, wherein the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

[0131]

[118] The use according to

[117] , wherein the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:63.

[0132]

[119] The use according to

[117] or

[118] , wherein the antibody-drug conjugate has a structure represented by the following formula: wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

[0133]

[120] The use according to any one of

[117] to

[119] , wherein the antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 in SEQ ID NO:69 and a light chain comprising the amino acid sequence of positions 21 to 233 in SEQ ID NO:61.

[0134]

[121] The use according to any one of

[117] to

[120] , wherein the heavy chain or light chain has undergone one or two or more modifications selected from the following: N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus.

[0135]

[122] The use according to any one of

[117] to

[121] , wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0136]

[123] The use according to any one of

[117] to

[122] , wherein the average number of units of the anti-tumor compound conjugated per antibody is in the range of 2 to 8.

[0137]

[124] The use according to any one of

[117] to

[123] , wherein the average number of units of the anti-tumor compound conjugated to each antibody is 7 to 8.

[0138]

[125] The use according to any one of

[117] to

[124] , wherein a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

[0139]

[126] The use according to any one of

[117] to

[124] , wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

[0140]

[127] The use according to any one of

[117] to

[124] , wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

[0141]

[128] The use according to any one of

[117] to

[124] , wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 8.0 mg / kg is administered to a subject suffering from cancer.

[0142]

[129] The use according to any one of

[117] to

[124] , wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 6.4 mg / kg is administered to a subject suffering from cancer.

[0143]

[130] The use according to any one of

[117] to

[124] , wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 8.0 mg / kg is administered to a subject suffering from cancer.

[0144]

[131] The use according to any one of

[117] to

[124] , wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 6.4 mg / kg is administered to a subject suffering from cancer.

[0145]

[132] The use according to any one of

[117] to

[124] , wherein a dose of about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg or about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0146]

[133] The use according to any one of

[117] to

[124] , wherein a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0147]

[134] The use according to any one of

[117] to

[124] , wherein a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0148]

[135] The use according to any one of

[117] to

[124] , wherein a dose of about 5.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0149]

[136] The use according to any one of

[117] to

[124] , wherein a dose of about 5.6 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0150]

[137] The use according to any one of

[117] to

[124] , wherein a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0151]

[138] The use according to any one of

[117] to

[124] , wherein a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0152]

[139] The use according to any one of

[117] to

[124] , wherein 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, or 6.4 mg / kg of the antibody-drug conjugate.

[0153]

[140] The use according to any one of

[117] to

[139] , wherein the antibody-drug conjugate is administered by intravenous administration.

[0154]

[141] The use according to any one of

[117] to

[140] , wherein the antibody-drug conjugate is administered once every 3 weeks.

[0155]

[142] The use according to any one of

[117] to

[141] , wherein the cancer is selected from renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, clear cell carcinoma of the ovary, endometrioid carcinoma of the ovary, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, nasopharyngeal carcinoma, prostate cancer or cancer associated with von Schiele-Lin disease.

[0156]

[143] The use according to

[142] , wherein the cancer is renal cell carcinoma, clear cell renal cell carcinoma or papillary renal cell carcinoma.

[0157]

[144] The use according to

[142] , wherein the cancer is ovarian cancer.

[0158]

[145] The use according to

[144] , wherein the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

[0159]

[146] The use according to any one of

[117] to

[145] , wherein the cancer is metastatic.

[0160]

[147] The use according to any one of

[117] to

[146] , wherein the cancer is resistant or refractory.

[0161]

[148] The use according to

[147] , wherein the resistance or refractory nature is resistance or refractory nature acquired by cancer due to treatment with an anticancer drug.

[0162]

[149] The use according to

[148] , wherein the anticancer drug is a platinum-based chemotherapy drug, a chemotherapy drug, a PARP inhibitor, an immune checkpoint inhibitor, an angiogenesis inhibitor or a VEGFR-TKI.

[0163]

[150] The use according to any one of

[117] to

[149] , wherein the subject has a history of treatment with one or two or more anti-cancer drugs selected from platinum-based chemotherapy drugs, chemotherapeutic drugs, PARP inhibitors, immune checkpoint inhibitors, angiogenesis inhibitors and VEGFR-TKIs.

[0164]

[151] The use according to

[148] , wherein the anticancer drug is a platinum-based chemotherapy drug.

[0165]

[152] The use according to

[151] , wherein the platinum-based chemotherapy drug comprises a platinum-based drug and a taxane.

[0166]

[153] The use according to any one of

[117] to

[152] , wherein the cancer is a cancer expressing CDH6.

[0167]

[154] The use according to

[153] , wherein the cancer expressing CDH6 is a cancer overexpressing CDH6.

[0168]

[155] The use according to any one of

[117] to

[154] , wherein the cancer is an inoperable or recurrent cancer.

[0169]

[156] The use according to any one of

[117] to

[155] , wherein the subject exhibits recurrence of cancer prior to administration of the antibody-drug conjugate.

[0170]

[157] The use according to

[156] , wherein recurrence of the cancer occurs within about six months or less of completing a chemotherapy regimen comprising a platinum-based drug.

[0171]

[158] The use according to

[156] , wherein recurrence of the cancer occurs within about six months or less of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0172]

[159] The use according to

[156] , wherein recurrence of the cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug.

[0173]

[160] The use according to

[156] , wherein recurrence of the cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0174]

[161] The use according to any one of

[117] to

[160] , wherein the subject's objective response rate is at least about 20%.

[0175]

[162] The use according to any one of

[117] to

[160] , wherein the subject's objective response rate is at least about 30%.

[0176]

[163] The use according to any one of

[117] to

[162] , wherein the progression-free survival of the subject after administration of the antibody-drug conjugate is at least 5 months.

[0177]

[164] The use according to any one of

[117] to

[162] , wherein the progression-free survival of the subject after administration of the antibody-drug conjugate is at least 5.5 months.

[0178]

[165] The use according to any one of

[117] to

[164] , wherein the antibody-drug conjugate is administered as a monotherapy.

[0179]

[166] The use according to any one of

[117] to

[164] , wherein the antibody-drug conjugate is administered to the subject together with a second drug.

[0180]

[167] The use according to

[166] , wherein the antibody-drug conjugate is administered before, after or simultaneously with the second drug.

[0181]

[168] The use according to any one of

[117] to

[160] , wherein the antibody-drug conjugate is administered as maintenance therapy.

[0182]

[169] The use according to any one of

[117] to

[160] , wherein the antibody-drug conjugate is administered as an adjuvant therapy.

[0183]

[170] The use according to any one of

[117] to

[160] , wherein the antibody-drug conjugate is administered after surgical resection of the tumor.

[0184]

[171] The use according to any one of

[117] to

[160] , wherein the antibody-drug conjugate is administered as an adjuvant tumor therapy.

[0185]

[172] The use according to any one of

[117] to

[160] , wherein the antibody-drug conjugate is administered prior to surgical resection of the tumor.

[0186]

[173] Use of an anti-CDH6 antibody-drug conjugate in the preparation of a drug for treating or preventing cancer, wherein the anti-CDH6 antibody-drug conjugate has a structure represented by the following formula: wherein AB represents an anti-CDH6 antibody or a functional fragment of the antibody, n represents the average number of units of a drug-linker structure conjugated to the antibody per antibody, and the antibody is connected to the linker via a thiol group derived from the antibody; and wherein the anti-CDH6 antibody-drug conjugate is a salt thereof or a hydrate of the anti-CDH6 antibody-drug conjugate or the salt, wherein the average number of units of the drug-linker structure conjugated to each antibody is 7 to 8, wherein the antibody comprises: a heavy chain amino acid sequence as shown in SEQ ID NO: 87 or an amino acid sequence derived from the amino acid sequence as shown in SEQ ID NO: 87 in which one or two amino acids are deleted from its carboxyl terminus; and a light chain amino acid sequence as shown in SEQ ID NO: 88, wherein the dosage of the antibody-drug conjugate is in the range of 1.6 mg / kg to 9.6 mg / kg, wherein the antibody-drug conjugate is administered by intravenous administration, wherein the antibody-drug conjugate is administered once every 3 weeks.

[0187]

[174] The use according to any one of

[117] to

[173] , wherein the antibody-drug conjugate is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable formulation component.

[0188] The present invention also includes the following aspects of the present invention: [1A] An anti-CDH6 antibody-drug conjugate for use in treating or preventing cancer, the antibody-drug conjugate comprising an anti-CDH6 antibody and an anti-tumor compound connected by a linker, wherein the linker and the anti-tumor compound are represented by the following formula: -(Succinimide-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) wherein -(Succinimide-3-yl-N)- has a structure represented by the following formula: [Formula 1] It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: [Formula 2] The nitrogen atom of the amino group at position 1 is a connection position, wherein the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

[0189] [2A] The antibody-drug conjugate according to [1A], wherein the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 63.

[0190] [3A] The antibody-drug conjugate according to [1A] or [2A], which has a structure represented by the following formula: [Formula 3] wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

[0191] [4A] The antibody-drug conjugate of any one of [1A] to [3A], wherein the antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 in SEQ ID NO:69 and a light chain comprising the amino acid sequence of positions 21 to 233 in SEQ ID NO:61.

[0192] [5A] The antibody-drug conjugate according to any one of [1A] to [4A], wherein the heavy chain or light chain has undergone one or two or more modifications selected from the following: N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus.

[0193] [6A] The antibody-drug conjugate according to any one of [1A] to [5A], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0194] [7A] The antibody-drug conjugate according to any one of [1A] to [6A], wherein the average number of units of the anti-tumor compound conjugated per antibody is in the range of 2 to 8.

[0195] [8A] The antibody-drug conjugate according to any one of [1A] to [7A], wherein the average number of units of the anti-tumor compound conjugated per antibody is 7 to 8.

[0196] [9A] The antibody-drug conjugate of any one of [1A] to [8A], wherein a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

[0197] [10A] The antibody-drug conjugate of any one of [1A] to [9A], wherein a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0198] [11A] The antibody-drug conjugate of any one of [1A] to [9A], wherein a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0199] [12A] The antibody-drug conjugate of any one of [1A] to [9A], wherein a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0200] [13A] The antibody-drug conjugate of any one of [1A] to [9A], wherein a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0201] [14A] The antibody-drug conjugate according to any one of [1A] to [13A], wherein the antibody-drug conjugate is administered by intravenous administration.

[0202] [15A] The antibody-drug conjugate according to any one of [1A] to [14A], wherein the antibody-drug conjugate is administered once every 3 weeks.

[0203] [16A] The antibody-drug conjugate of any one of [1A] to [15A], wherein the cancer is selected from renal cell carcinoma, clear cell renal carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, bile duct carcinoma, lung cancer, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor or neuroblastoma.

[0204] [17A] The antibody-drug conjugate of [16A], wherein the cancer is renal cell carcinoma.

[0205] [18A] The antibody-drug conjugate of [16A], wherein the cancer is ovarian cancer.

[0206] [19A] The antibody-drug conjugate of any one of [1A] to [18A], wherein the cancer is resistant or refractory.

[0207] [20A] The antibody-drug conjugate according to [19A], wherein the resistance or refractory nature is resistance or refractory nature acquired by cancer due to treatment with an anticancer drug.

[0208] [21A] The antibody-drug conjugate according to [20A], wherein the anticancer drug is a platinum-based chemotherapy drug, chemotherapy, a PARP inhibitor, an immune checkpoint inhibitor, an angiogenesis inhibitor or a VEGFR-TKI.

[0209] [22A] The antibody-drug conjugate according to [20A], wherein the anticancer drug is a platinum-based chemotherapy drug.

[0210] [23A] The antibody-drug conjugate according to [22A], wherein the platinum-based chemotherapy drug comprises a platinum-based drug and a taxane.

[0211] [24A] The antibody-drug conjugate of any one of [1A] to [23A], wherein the cancer is a cancer expressing CDH6.

[0212] [25A] The antibody-drug conjugate of [24A], wherein the CDH6-expressing cancer is a CDH6-overexpressing cancer.

[0213] [26A] The antibody-drug conjugate of any one of [1A] to [25A], wherein the cancer is an inoperable or recurrent cancer.

[0214] [27A] A pharmaceutical composition comprising the antibody-drug conjugate or a salt thereof according to any one of [1A] to [26A] as an active ingredient, and a pharmaceutically acceptable formulation component.

[0215] [28A] A method for treating or preventing cancer in a subject, comprising administering to a subject having cancer an anti-CDH6 antibody-drug conjugate, wherein the anti-CDH6 antibody-drug conjugate comprises an anti-CDH6 antibody and an anti-tumor compound connected by a linker, wherein the linker and the anti-tumor compound are represented by the following formula: -(Succinimide-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) wherein -(Succinimide-3-yl-N)- has a structure represented by the following formula: [Formula 4] It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: [Formula 5] The nitrogen atom of the amino group at position 1 is a connection position, wherein the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

[0216] [29A] The method according to [28A], wherein the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:63.

[0217] [30A] The method according to [28A] or [29A], wherein the antibody-drug conjugate has a structure represented by the following formula: [Formula 6] wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

[0218] [31A] The method according to any one of [28A] to [30A], wherein the antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 in SEQ ID NO:69 and a light chain comprising the amino acid sequence of positions 21 to 233 in SEQ ID NO:61.

[0219] [32A] The method according to any one of [28A] to [31A], wherein the heavy chain or light chain has undergone one or two or more modifications selected from the following: N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus.

[0220] [33A] The method according to any one of [28A] to [32A], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0221] [34A] The method according to any one of [28A] to [33A], wherein the average number of units of the anti-tumor compound conjugated per antibody is in the range of 2 to 8.

[0222] [35A] The method according to any one of [28A] to [33A], wherein the average number of units of the anti-tumor compound conjugated per antibody is 7 to 8.

[0223] [36A] The method of any one of [28A] to [35A], wherein a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to the subject suffering from cancer.

[0224] [37A] The method of any one of [28A] to [35A], wherein a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0225] [38A] The method of any one of [28A] to [35A], wherein a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to the subject suffering from cancer.

[0226] [39A] The method of any one of [28A] to [35A], wherein a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to the subject suffering from cancer.

[0227] [40A] The method of any one of [28A] to [35A], wherein a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0228] [41A] The method according to any one of [28A] to [40A], wherein the antibody-drug conjugate is administered by intravenous administration.

[0229] [42A] The method of any one of [28A] to [41A], wherein the antibody-drug conjugate is administered once every 3 weeks.

[0230] [43A] The method of any one of [28A] to [42A], wherein the cancer is selected from renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, bile duct cancer, lung cancer, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, or neuroblastoma.

[0231] [44A] The method of [43A], wherein the cancer is renal cell carcinoma.

[0232] [45A] The method of [43A], wherein the cancer is ovarian cancer.

[0233] [46A] The method of any one of [28A] to [45A], wherein the cancer is resistant or refractory.

[0234] [47A] The method according to [46A], wherein the resistance or refractory nature is resistance or refractory nature acquired by cancer due to treatment with an anticancer drug.

[0235] [48A] The method according to [47A], wherein the anticancer drug is a platinum-based chemotherapy drug, chemotherapy, a PARP inhibitor, an immune checkpoint inhibitor, an angiogenesis inhibitor or a VEGFR-TKI.

[0236] [49A] The method according to [47A], wherein the anticancer drug is a platinum-based chemotherapy drug.

[0237] [50A] The method according to [49A], wherein the platinum-based chemotherapy drug comprises a platinum-based drug and a taxane.

[0238] [51A] The method of any one of [28A] to [50A], wherein the cancer is a cancer expressing CDH6.

[0239] [52A] The method according to [51A], wherein the cancer expressing CDH6 is a cancer overexpressing CDH6.

[0240] [53A] The method of any one of [28A] to [52A], wherein the cancer is an inoperable or recurrent cancer.

[0241] [54A] The method of any one of [28A] to [53A], wherein the antibody-drug conjugate is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable formulation component.

[0242] [55A] Use of an anti-CDH6 antibody-drug conjugate in the preparation of a drug for treating or preventing cancer, wherein the antibody-drug conjugate comprises an anti-CDH6 antibody and an anti-tumor compound connected by a linker, wherein the linker and the anti-tumor compound are represented by the following formula: -(Succinimide-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) wherein -(Succinimide-3-yl-N)- has a structure represented by the following formula: [Formula 7] It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: [Formula 8] The nitrogen atom of the amino group at position 1 is a connection position, wherein the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

[0243] [56A] The use according to [55A], wherein the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:63.

[0244] [57A] The use according to [55A] or [56A], wherein the antibody-drug conjugate has a structure represented by the following formula: [Formula 9] wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

[0245] [58A] The use according to any one of [55A] to [57A], wherein the antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 in SEQ ID NO:69 and a light chain comprising the amino acid sequence of positions 21 to 233 in SEQ ID NO:61.

[0246] [59A] The use according to any one of [55A] to [58A], wherein the heavy chain or light chain has undergone one or two or more modifications selected from the following: N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus.

[0247] [60A] The use according to any one of [55A] to [59A], wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0248] [61A] The use according to any one of [55A] to [60A], wherein the average number of units of the anti-tumor compound conjugated per antibody is in the range of 2 to 8.

[0249] [62A] The use according to any one of [55A] to [61A], wherein the average number of units of the anti-tumor compound conjugated per antibody is 7 to 8.

[0250] [63A] The use according to any one of [55A] to [62A], wherein a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

[0251] [64A] The use according to any one of [55A] to [63A], wherein a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0252] [65A] The use according to any one of [55A] to [63A], wherein a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0253] [66A] The use according to any one of [55A] to [63A], wherein a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0254] [67A] The use according to any one of [55A] to [63A], wherein a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

[0255] [68A] The use according to any one of [55A] to [67A], wherein the antibody-drug conjugate is administered by intravenous administration.

[0256] [69A] The use according to any one of [55A] to [68A], wherein the antibody-drug conjugate is administered once every 3 weeks.

[0257] [70A] The use according to any one of [55A] to [69A], wherein the cancer is selected from renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, bile duct cancer, lung cancer, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor or neuroblastoma.

[0258] [71A] The use according to [70A], wherein the cancer is renal cell carcinoma.

[0259] [72A] The antibody-drug conjugate of [70A], wherein the cancer is ovarian cancer.

[0260] [73A] The use according to any one of [55A] to [72A], wherein the cancer is resistant or refractory.

[0261] [74A] The use according to [73A], wherein the resistance or refractory nature is resistance or refractory nature acquired by cancer due to treatment with an anticancer drug.

[0262] [75A] The use according to [74A], wherein the anticancer drug is a platinum-based chemotherapy drug, chemotherapy, a PARP inhibitor, an immune checkpoint inhibitor, an angiogenesis inhibitor or a VEGFR-TKI.

[0263] [76A] The use according to [74A], wherein the anticancer drug is a platinum-based chemotherapy drug.

[0264] [77A] The use according to [76A], wherein the platinum-based chemotherapy drug comprises a platinum-based drug and a taxane.

[0265] [78A] The use according to any one of [55A] to [77A], wherein the cancer is a cancer expressing CDH6.

[0266] [79A] The use according to [78A], wherein the cancer expressing CDH6 is a cancer overexpressing CDH6.

[0267] [80A] The use according to any one of [55A] to [79A], wherein the cancer is an inoperable or recurrent cancer.

[0268] [81A] The use according to any one of [55A] to [80A], wherein the antibody-drug conjugate is administered as a pharmaceutical composition comprising at least one pharmaceutically acceptable formulation component.

[0269] In some aspects, the present disclosure provides an anti-CDH6 antibody-drug conjugate for use in treating or preventing cancer, the antibody-drug conjugate comprising an anti-CDH6 antibody and an anti-tumor compound connected by a linker.

[0270] In some aspects, the disclosure provides methods of treating or preventing cancer in a subject, comprising administering to the subject having cancer an anti-CDH6 antibody-drug conjugate comprising an anti-CDH6 antibody and an anti-tumor compound connected by a linker.

[0271] In some aspects, the present disclosure provides use of an anti-CDH6 antibody-drug conjugate in the preparation of a medicament for treating or preventing cancer, wherein the antibody-drug conjugate comprises an anti-CDH6 antibody and an anti-tumor compound connected by a linker.

[0272] In some aspects, the present disclosure provides a pharmaceutical composition for treating or preventing cancer, comprising an anti-CDH6 antibody-drug conjugate as an active ingredient, wherein the antibody-drug conjugate comprises an anti-CDH6 antibody and an anti-tumor compound connected by a linker.

[0273] In some embodiments, the linker and the anti-tumor compound are represented by the following formula: -(Succinimide-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) wherein -(Succinimide-3-yl-N)- has a structure represented by the following formula: [Formula 10] It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: [Formula 11] The nitrogen atom of the amino group at position 1 is the connection position.

[0274] In some aspects, the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

[0275] In some aspects, the anti-CDH6 antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:63.

[0276] In some aspects, the antibody-drug conjugate has the structure shown by the following formula: [Formula 12] wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

[0277] In some aspects, the anti-CDH6 antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 of SEQ ID NO:69 and a light chain comprising the amino acid sequence of positions 21 to 233 of SEQ ID NO:61.

[0278] In some aspects, the heavy chain or light chain has undergone two or more modifications selected from the following: N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus.

[0279] In some aspects, the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

[0280] In some aspects, the average number of units of the selected drug-linker structure conjugated per antibody is in the range of 1 to 10. In some aspects, the average number of units of the selected drug-linker structure conjugated per antibody is in the range of 2 to 8. In some aspects, the average number of units of the selected drug-linker structure conjugated per antibody is in the range of 5 to 8. In some aspects, the average number of units of the selected drug-linker structure conjugated per antibody is in the range of 7 to 8.

[0281] In some aspects, a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to a subject with cancer. In some aspects, a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 9.6 mg / kg is administered to a subject with cancer. In some aspects, a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 9.6 mg / kg is administered to a subject with cancer. In some aspects, a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 8.0 mg / kg is administered to a subject with cancer. In some aspects, a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 6.4 mg / kg is administered to a subject with cancer. In some aspects, a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 8.0 mg / kg is administered to a subject with cancer. In some aspects, a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 6.4 mg / kg is administered to a subject with cancer. In some aspects, a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject with cancer. In some aspects, a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to a subject with cancer. In some aspects, a dose of about 5.4 mg / kg of the antibody-drug conjugate is administered to a subject with cancer. In some aspects, a dose of about 5.6 mg / kg of the antibody-drug conjugate is administered to a subject with cancer. In some aspects, a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to a subject with cancer. In some aspects, a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject with cancer. In some aspects, a dose of about 9.6 mg / kg of the antibody-drug conjugate is administered to a subject with cancer.

[0282] In some aspects, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 In some embodiments, the present invention provides a dosage of the antibody-drug conjugate of at least 60 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg or 6.4 mg / kg.

[0283] In some aspects, the antibody-drug conjugate is administered by intravenous administration.

[0284] In some aspects, the antibody-drug conjugate is administered once every 3 weeks.

[0285] In some aspects, the cancer is selected from renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, ovarian endometrioid carcinoma, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, nasopharyngeal carcinoma, prostate cancer or a cancer related to von schie-lin disease. In some aspects, the cancer is selected from renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, bile duct cancer, lung cancer, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor and neuroblastoma. In some aspects, the cancer is ovarian cancer. In some aspects, ovarian cancer is epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In some aspects, cancer is metastatic. In some aspects, cancer is renal cell carcinoma, renal clear cell carcinoma, or papillary renal cell carcinoma. In some aspects, cancer is renal cell carcinoma.

[0286] In some aspects, cancer is resistant or refractory. In some aspects, resistance or refractory is the resistance or refractory that cancer obtains due to treatment with anticancer drugs. In some aspects, anticancer drugs are chemotherapy drugs based on platinum, chemotherapy drugs, poly ADP ribose polymerase (PARP) inhibitors, immune checkpoint inhibitors (ICI), angiogenesis inhibitors or vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKI). In some aspects, anticancer drugs are chemotherapy drugs based on platinum. In some aspects, chemotherapy drugs based on platinum include drugs based on platinum and taxanes.

[0287] In some aspects, the subject has a cancer that is resistant to platinum-based chemotherapy. In some aspects, the subject exhibits recurrence of cancer prior to administration of the ADC. In some aspects, the subject has a cancer that is resistant or refractory to a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0288] In some aspects, the recurrence of cancer occurs in less than or within about six months of completing a chemotherapy regimen comprising a platinum-based drug. In some aspects, the recurrence of cancer occurs in less than about six months of completing a chemotherapy regimen comprising a platinum-based drug. In some aspects, the recurrence of cancer occurs in less than about six months of completing a chemotherapy regimen comprising a platinum-based drug.

[0289] In some aspects, recurrence of cancer occurs in less than or within about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. In some aspects, recurrence of cancer occurs in less than about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. In some aspects, recurrence of cancer occurs in less than about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0290] In some aspects, recurrence of cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug. In some aspects, recurrence of cancer occurs within about six months of completing a chemotherapy regimen comprising a platinum-based drug. In some aspects, recurrence of cancer occurs after about six months of completing a chemotherapy regimen comprising a platinum-based drug.

[0291] In some aspects, recurrence of cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. In some aspects, recurrence of cancer occurs within about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. In some aspects, recurrence of cancer occurs after about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0292] In some aspects, the recurrence of cancer occurs within or less than six months of completing a chemotherapy regimen comprising a platinum-based drug. In some aspects, the recurrence of cancer occurs within or less than six months of completing a chemotherapy regimen comprising a platinum-based drug. In some aspects, the recurrence of cancer occurs within six months of completing a chemotherapy regimen comprising a platinum-based drug.

[0293] In some aspects, recurrence of cancer occurs in less than six months or within six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. In some aspects, recurrence of cancer occurs in less than six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. In some aspects, recurrence of cancer occurs in less than six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0294] In some aspects, recurrence of cancer occurs within or after six months of completing a chemotherapy regimen comprising a platinum-based drug. In some aspects, recurrence of cancer occurs within six months of completing a chemotherapy regimen comprising a platinum-based drug. In some aspects, recurrence of cancer occurs after six months of completing a chemotherapy regimen comprising a platinum-based drug.

[0295] In some aspects, recurrence of cancer occurs within or after six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. In some aspects, recurrence of cancer occurs within six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane. In some aspects, recurrence of cancer occurs after six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

[0296] In some aspects, the subject suffers from cancer that is resistant or refractory to poly ADP ribose polymerase (PARP) inhibitors. In some aspects, the subject suffers from cancer that is resistant or refractory to immune checkpoint inhibitors (ICIs). In some aspects, the subject suffers from cancer that is resistant or refractory to angiogenesis inhibitors. In some aspects, the subject suffers from cancer that is resistant or refractory to vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKIs).

[0297] In some aspects, the subject has a history of treatment with one or two or more anti-cancer drugs selected from platinum-based chemotherapy drugs, chemotherapeutic drugs, PARP inhibitors, immune checkpoint inhibitors, angiogenesis inhibitors, and VEGFR-TKIs.

[0298] In some aspects, the cancer comprises one or more tumors expressing CDH6. In some aspects, the cancer expressing CDH6 is a cancer that overexpresses CDH6. In some aspects, the cancer that overexpresses CDH6 is a cancer that gives a high score for CDH6 expression in an immunohistochemical method. In some aspects, the cancer that overexpresses CDH6 is a cancer that gives a high score for CDH6 expression in an in situ hybridization method. In some aspects, the cancer that overexpresses CDH6 is a cancer that gives a high score for CDH6 expression in a next generation sequencing method.

[0299] In some aspects, the cancer is an inoperable or recurrent cancer.

[0300] In some aspects, the objective remission rate of the subject of the ADC of the treatment effective amount is at least about 20%. In some aspects, the objective remission rate of the subject of the ADC of the treatment effective amount is at least about 30%. In some aspects, the objective remission rate of the subject of the ADC of the treatment effective amount is at least about 40%. In some aspects, the objective remission rate of the subject of the ADC of the treatment effective amount is at least about 50%. In some aspects, the objective remission rate of the subject of the ADC of the treatment effective amount is at least about 60%.

[0301] In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 5 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 5.5 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 5.6 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 5.8 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 6.0 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 7.0 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 7.9 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 8 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 9 months. In some aspects, the progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 10 months. In some aspects, the progression-free survival of a subject administered a therapeutically effective amount of ADC is at least about 11 months. In some aspects, the progression-free survival of a subject administered a therapeutically effective amount of ADC is at least about 12 months. In some aspects, the progression-free survival of a subject administered a therapeutically effective amount of ADC is at least about 13 months. In some aspects, the progression-free survival of a subject administered a therapeutically effective amount of ADC is at least about 13.9 months.

[0302] In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 5 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 5.5 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 5.6 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 5.8 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 6.0 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 7.0 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 7.9 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 8 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 9 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 10 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 11 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 12 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 13 months. In some aspects, the median progression-free survival of the subject of the ADC administered with a therapeutically effective amount is at least about 13.9 months.

[0303] In some aspects, the ADC is administered to a subject as a monotherapy.

[0304] In some aspects, the ADC is administered to the subject together with a second drug. In some aspects, the ADC is administered before the second drug. In some aspects, the ADC is administered after the second drug. In some aspects, the ADC is administered simultaneously with the second drug.

[0305] In some aspects, the ADC is administered to the subject as maintenance therapy.

[0306] In some aspects, the ADC is administered to a subject as an adjuvant therapy. In some aspects, the ADC is administered to a subject after surgical resection of a tumor.

[0307] In some aspects, the ADC is administered to a subject as an adjuvant therapy for a tumor. In some aspects, the ADC is administered to a subject prior to surgical removal of a tumor.

[0308] In some aspects, the disclosure generally relates to an anti-CDH6 antibody-drug conjugate (ADC) for use in treating or preventing cancer, the ADC having a structure shown by the following formula: wherein AB represents an anti-CDH6 antibody or a functional fragment of the antibody, n represents the average number of units of a drug-linker structure conjugated to the antibody per antibody, and the antibody is connected to the linker via a thiol group derived from the antibody; and wherein the ADC is a salt thereof or a hydrate of the ADC or the salt, wherein the average number of units of the drug-linker structure conjugated to each antibody is 7 to 8, wherein the antibody comprises: a heavy chain amino acid sequence as shown in SEQ ID NO: 87 or an amino acid sequence derived from the amino acid sequence as shown in SEQ ID NO: 87 in which one or two amino acids are deleted from its carboxyl terminus; and a light chain amino acid sequence as shown in SEQ ID NO: 88, wherein the dosage of the antibody-drug conjugate is in the range of 1.6 mg / kg to 8.0 mg / kg, wherein the antibody-drug conjugate is administered by intravenous administration, wherein the antibody-drug conjugate is administered once every 3 weeks.

[0309] Also provided herein is a pharmaceutical composition containing the antibody-drug conjugate or a salt thereof according to any one of the aforementioned aspects or embodiments as an active ingredient, and a pharmaceutically acceptable formulation component.

[0310] The foregoing general description and the following detailed description are exemplary and explanatory, and are intended to provide further explanation of the disclosure claimed. For those skilled in the art, other objects, advantages and new features will be readily apparent from the following brief description of the drawings and the detailed description of the disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0311] [ Figure 1 ] Figure 1 The design of a Phase 1 study for the treatment of renal cell carcinoma (RCC) and ovarian cancer (OVC) is shown.

[0312] [ Figure 2 ] Figure 2 Patient demographics and baseline characteristics of the dose escalation portion of the Phase 1 study are shown.

[0313] [ Figure 3 ] Figure 3 Shown are the numbers of patients in the dose-escalation portion of the Phase 1 study who had treatment-emergent adverse events (TEAEs), regardless of causality, that occurred in ≥10% of patients.

[0314] [ Figure 4 ] Figure 4The number of patients in the dose escalation portion of the Phase 1 study who had treatment-emergent adverse events (TEAEs) related to DS-6000a, which occurred in ≥10% of patients, are shown.

[0315] [ Figure 5 ] Figure 5 Tumor responses of subjects (n=24) in the dose escalation portion of the Phase 1 study are shown.

[0316] [ Figure 6 ] Figure 6 The percentage change from baseline in the total number of target lesions in the dose escalation portion of the Phase 1 study is shown. The top graph shows a spider plot including all dosing groups. The bottom graph shows a spider plot divided into each dosing group.

[0317] [ Figure 7 ] Figure 7 CA-125 responses of OVC subjects (n=17) in the dose escalation portion of the Phase 1 study are shown.

[0318] [ Figure 8 ] Figure 8 The percentage change from baseline in CA-125 in the dose escalation portion of the Phase 1 study is shown. The top graph shows a spider plot including all dosing groups. The bottom graph shows a spider plot separated into each dosing group.

[0319] [ Fig. 9 ] Fig. 9 A reduction in the size of target lesions was shown in RCC patients treated with 3.2 mg / kg of DS-6000a.

[0320] [ Fig.10 ] Fig.10 A reduction in the size of target lesions was shown in OVC patients treated with 6.4 mg / kg of DS-6000a.

[0321] [ Fig.11 ] Fig.11 The best percent change from baseline in the total longest dimension in the dose escalation portion of the Phase 1 study is shown.

[0322] [ Fig.12 ] Fig.12 An updated phase 1 study design for the treatment of RCC and OVC is shown.

[0323] [ Fig.13 ] Fig.13 Patient demographics and baseline characteristics for the dose escalation and expansion portions of the Phase 1 study are shown.

[0324] [ Fig.14 ] Fig.14 The number of patients with TEAEs, regardless of causality, occurring in ≥15% of patients in the dose-escalation and expansion portions of the Phase 1 study are shown.

[0325] [ Fig.15 ] Fig.15 The best percent change from baseline in the total of the longest dimension of the OVC body in the dose escalation and expansion portions of the Phase 1 study is shown.

[0326] [ Fig.16 ] Fig.16 The percentage change from baseline in the total number of OVC subject target lesions in the dose escalation and expansion portions of the Phase 1 study is shown. The top graph shows a spider plot that includes all dosing groups. The bottom graph shows a spider plot that is separated into each dosing group.

[0327] [ Fig.17 ] Fig.17 The best overall tumor response was shown for OVC subjects (n=44) in the dose escalation and expansion portion of the Phase 1 study.

[0328] [ Fig.18 ] Fig.18 The percentage change from baseline in CA-125 for OVC subjects in the dose escalation and expansion portion of the Phase 1 study is shown. The top graph shows a spider graph including all dosing groups. The bottom graph shows a spider graph separated into each dosing group.

[0329] [ Fig.19 ] Fig.19 The best percent change from baseline in CA-125 for OVC subjects in the dose-escalation and expansion portions of the Phase 1 study is shown.

[0330] [ Fig. 20 ] Fig. 20 Progression-free survival is shown for OVC subjects in the dose-escalation and expansion portions of the phase 1 study.

[0331] [ Fig.21 ] Fig.21 Objective response rates are shown for OVC subjects in the dose-escalation and expansion portions of the phase 1 study. DETAILED DESCRIPTION

[0332] Hereinafter, preferred embodiments for implementing the disclosed methods and uses will be described with reference to the accompanying drawings. It should be noted that the embodiments described below are merely exemplary of representative embodiments, and the scope of the present disclosure should not be narrowly interpreted due to these examples.

[0333] It should be understood that the method is not limited to the specific embodiments described, and therefore may vary. It should also be understood that the terminology used herein is only for the purpose of describing specific embodiments, and is not intended to be limiting. The scope of the present technology is limited only by the appended claims.

[0334] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used to practice or test the disclosed methods and uses, representative illustrative methods and materials are now described.

[0335] When a range of values ​​is provided, it is understood that each intermediate value between the upper and lower limits of the range, unless the context clearly dictates otherwise, to one-tenth of the base of the lower limit, and any other specified value or intermediate value within the specified range are included in the disclosure. Subject to any specific excluded limits in the specified range, the upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also included in the disclosure. When a specified range includes one or two limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0336] As used in the specification and claims, the singular form "a," "an," and "the" include singular and plural references unless the context clearly dictates otherwise.

[0337] As used herein, the term "comprising" is intended to mean that compositions and methods include the recited elements, but do not exclude other elements. "Consisting essentially of" when used to define compositions and methods should be intended to exclude other elements that have any significance for the composition or method. "Consisting of" should be intended to exclude trace elements of other ingredients more than the claimed composition as well as substantial method steps. The embodiments defined by each of these transition terms are within the scope of the present disclosure. Therefore, the methods and compositions are intended to include additional steps and components (comprising), or on the other hand include insignificant steps and compositions (consisting essentially of), or on the other hand only the stated method steps or compositions are intended (consisting of).

[0338] As used herein, "about" means plus or minus 10% as well as the specified number. For example, "about 10" should be understood as both "10" and "9-11".

[0339] As used herein, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0340] The terms "individual", "subject" and "patient" are used interchangeably herein and refer to any individual mammal, e.g., bovine, canine, feline, equine, simian, porcine, camelid, bat or human, that is treated according to the disclosed methods or uses. In a preferred embodiment, the subject is a human.

[0341] As used herein, the phrases "effective amount," "therapeutically effective amount," and "therapeutic level" mean a dose or concentration that provides a specific pharmacological effect in a subject for which the ADC is administered to a subject in need of such treatment, i.e., to treat or prevent cancer (e.g., renal cell carcinoma, ovarian cancer, cancer expressing CDH6, or resistant or refractory cancer). It is emphasized that a therapeutically effective amount or therapeutic level of an ADC will not always be effective in treating the cancers described herein, even if such a dose is considered by one skilled in the art to be a therapeutically effective amount. For convenience only, exemplary doses, drug delivery amounts, therapeutically effective amounts, and therapeutic levels are provided below. One skilled in the art may adjust such amounts in accordance with standard practice as required for the treatment of a particular subject and / or condition. The therapeutically effective amount may vary based on the route of administration and dosage form, the age and weight of the subject, and / or the condition of the subject (including the type and severity of the cancer).

[0342] As used herein, the terms "treatment" or "treating" with respect to cancer refer to reducing, inhibiting, or eliminating cancer; reducing, inhibiting, or eliminating cancer cell growth; reducing, inhibiting, or eliminating cancer spread; or causing tumor or metastasis regression or death. Treatment and treating may also optionally mean improving the quality of life or overall survival of a subject, even if cancer cell growth is not inhibited and / or cancer is not dead.

[0343] As used herein, the terms "prevent" or "preventing" with respect to cancer refer to delaying or preventing the occurrence of metastasis (i.e., growth of cancer at secondary sites where the cancer was not present when treatment was initiated), as well as delaying or preventing the recurrence of cancer if the subject achieves remission or the cancer / tumor is completely destroyed or killed.

[0344] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0345] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, such as phosphate buffered saline, water, emulsions (such as, for example, oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15th Edition, Mack Publ. Co., Easton, PA

[1975] .

[0346] The phrases "parenteral administration" and "parenterally administered" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0347] As used herein, the phrases "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered" mean administration of a compound, drug, or other material other than directly into the central nervous system, such that it enters the patient's system and thereby undergoes metabolism and other similar processes, e.g., subcutaneous administration.

[0348] In this specification, the term "cancer" is used to have the same meaning as the term "tumor".

[0349] In this specification, the term "gene" is used to include not only DNA but also mRNA and cDNA thereof, and cRNA thereof.

[0350] In this specification, the term "polynucleotide" or "nucleotide" is used to have the same meaning as nucleic acid, and also includes DNA, RNA, probes, oligonucleotides and primers. In this specification, unless otherwise specified, the terms "polynucleotide" and "nucleotide" can be used interchangeably.

[0351] In the present specification, the terms "polypeptide" and "protein" can be used interchangeably with each other.

[0352] In the present specification, the term "cell" includes cells in individual animals as well as cultured cells.

[0353] In the present specification, the term "CDH6" may be used to have the same meaning as CDH6 protein. In the present specification, human CDH6 is also referred to as "hCDH6".

[0354] In this specification, the term "cytotoxic activity" is used to mean pathological changes caused to cells in any given manner. The term means not only direct trauma, but also all types of structural or functional damage caused to cells, such as DNA cleavage, formation of base dimers, chromosome cleavage, damage to cell mitotic apparatus, and reduction in the activity of various types of enzymes.

[0355] In this specification, the phrase "exerts toxicity in cells" is used to mean that toxicity is manifested in cells in any given manner. The term means not only direct trauma, but also all types of structural, functional or metabolic effects on cells, such as DNA cleavage, formation of base dimers, chromosome cleavage, damage to the cell mitotic apparatus, reduction in the activity of various types of enzymes, and inhibition of the action of cell growth factors.

[0356] In this specification, "functional fragment of an antibody", also referred to as "antigen-binding fragment of an antibody", is used to refer to a partial fragment of an antibody having binding activity against an antigen, and includes Fab, F(ab')2, scFv, diabodies, linear antibodies, and multispecific antibodies formed by antibody fragments, etc. Fab', which is a monovalent fragment of an antibody variable region obtained by treating F(ab')2 under reducing conditions, is also included in the antigen-binding fragment of an antibody. However, the antigen-binding fragment of an antibody is not limited to these molecules, as long as the antigen-binding fragment has antigen-binding ability. These antigen-binding fragments include not only those obtained by treating the full-length molecules of an antibody protein with an appropriate enzyme, but also proteins produced in appropriate host cells using genetically engineered antibody genes.

[0357] In this specification, the term "epitope" is used to refer to a partial peptide or partial three-dimensional structure of CDH6 to which a specific anti-CDH6 antibody binds. This epitope as a partial peptide of the above-mentioned CDH6 can be determined by methods well known to those skilled in the art, such as immunoassays. First, various partial structures of the antigen are generated. Regarding the generation of this partial structure, known oligopeptide synthesis techniques can be applied. For example, a series of polypeptides are produced by genetic recombination techniques well known to those skilled in the art, in which CDH6 has been continuously truncated from its C-terminus or N-terminus with a suitable length. Thereafter, the reactivity of the antibody to this polypeptide is studied, and the recognition site is roughly determined. Thereafter, further shorter peptides are synthesized, and their reactivity to these peptides can then be studied to determine the epitope. When an antibody that binds to a membrane protein having multiple extracellular domains is directed to a three-dimensional structure consisting of multiple domains as an epitope, the domain to which the antibody binds can be determined by modifying the amino acid sequence of a specific extracellular domain, and thereby modifying the three-dimensional structure. The epitope of the partial three-dimensional structure of the antigen that binds to a specific antibody can also be determined by describing in detail the amino acid residues of the antigen adjacent to the antibody by X-ray structural analysis.

[0358] In this specification, the phrase "antibody binding to the same epitope" is used to mean an antibody binding to a common epitope. If the second antibody binds to a partial peptide or a partial three-dimensional structure that the first antibody binds to, it can be determined that the first antibody and the second antibody bind to the same epitope. On the other hand, even if the specific sequence or structure of the epitope has not yet been determined, it can be determined that the first antibody and the second antibody bind to the same epitope by confirming that the second antibody competes with the first antibody for the binding of the first antibody to the antigen (that is, the second antibody interferes with the binding of the first antibody to the antigen). In this specification, the phrase "binding to the same epitope" refers to a situation in which the first antibody and the second antibody bind to a common epitope by any one or both of these determination methods. When the first antibody and the second antibody bind to the same epitope and further, the first antibody has a special effect such as anti-tumor activity or internalization activity, it can be expected that the second antibody has the same activity as the activity of the first antibody.

[0359] In this specification, the term "CDR" is used to refer to the complementarity determining region. The heavy chain and light chain of known antibody molecules each have three CDRs. This CDR is also called a hypervariable region and is located in the variable region of the heavy chain and light chain of the antibody. These regions have a particularly highly variable primary structure and are separated into three positions on the primary structure of each polypeptide chain of the heavy chain and light chain. In this specification, with respect to the CDR of an antibody, the CDRs of the heavy chain are respectively referred to as CDRH1, CDRH2 and CDRH3 from the amino-terminal side of the amino acid sequence of the heavy chain, and the CDRs of the light chain are respectively referred to as CDRL1, CDRL2 and CDRL3 from the amino-terminal side of the amino acid sequence of the light chain. These positions are located close to each other in the three-dimensional structure and determine the specificity of the antibody to the antigen (the antibody binds to it).

[0360] In the present disclosure, the phrase "hybridizes under stringent conditions" is used to mean that hybridization is performed in a commercially available hybridization solution ExpressHyb hybridization solution (manufactured by Clontech Laboratories, Inc.) at 68°C, or hybridization is performed under conditions or conditions equivalent thereto, wherein hybridization is performed at 68°C in the presence of 0.7-1.0 M NaCl using a DNA-immobilized filter, and then the resultant is washed at 68°C with a 0.1- to 2-fold concentration SSC solution (wherein 1-fold concentration SSC consists of 150 mM NaCl and 15 mM sodium citrate) for identification.

[0361] In the present specification, the term "one to several" is used to mean 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 or 2.

[0362] In this specification, the term "anticancer drug" is used to refer to a drug used to suppress, prevent, inhibit and / or slow down the proliferation, growth and / or spread of cancer cells or tumor cells. In this specification, the term "anticancer drug" has the same meaning as the term "anticancer agent", "antitumor agent" or "antitumor drug".

[0363] In this specification, the term "resistant" is used to mean no response to treatment with anticancer drugs. The term may also be expressed as "refractory", "non-responsive" or "unresponsive". In addition, the term may also be expressed as "intolerant", because tumor growth cannot be prevented due to the nature of non-responsiveness. In this specification, the term "resistant" may also be used when the subject's cancer shows low sensitivity to treatment with anticancer drugs after treatment with anticancer drugs, cancer cells do not disappear or shrink, CR or PR is not achieved, and / or cancer cells progress early (e.g., with respect to ovarian cancer, in less than 6 months or within 6 months).

[0364] In the present specification, “resistant” may be “cancer has resistance acquired due to treatment with an anticancer drug”, or may be “cancer has inherent resistance independent of treatment with an anticancer drug”.

[0365] In this specification, the term "chemotherapy" is used to refer to therapy using one or more chemotherapeutic drugs for treating cancer.

[0366] In this specification, the term "chemotherapeutic drug" is used to refer to a chemotherapeutic agent used to treat cancer. Chemotherapeutic drugs include, but are not limited to, alkylating agents (e.g., nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, hexamethylmelamine, thiotepa, busulfan, carmustine, lomustine, semustine, streptozotocin, dacarbazine), antimetabolites (e.g., gemcitabine, methotrexate, fluorouracil, deoxyfluridine, capecitabine, floxuridine, cytarabine, mercaptopurine, thioguanine, pentotstatin), vinca alkaloids (e.g., vinblastine, vincristine), epidermal growth factor (EPF), cytochrome P400, cytochrome C400, cytochrome P ... Acetotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), platinum complexes (e.g., cisplatin, carboplatin, oxaliplatin), taxanes (e.g., paclitaxel, docetaxel), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazines (e.g., procarbazine hydrochloride), vitamin A metabolites (e.g., retinoic acid) and pharmacologically acceptable salts thereof.

[0367] In this specification, the term "platinum-based chemotherapy" is used to refer to cancer therapy using one or more platinum-based drugs with or without one or more other chemotherapeutic drugs.

[0368] In this specification, the term "platinum-based chemotherapeutic drug" is used to mean a platinum-based drug or a group of drugs used in platinum-based chemotherapy.

[0369] In this specification, the term "platinum-based drug" is used to refer to a platinum complex used to treat cancer. Platinum-based drugs include, but are not limited to, cisplatin, carboplatin, and oxaliplatin.

[0370] In the present specification, the term "PARP inhibitor" is used to mean a drug having the function of inhibiting PARP (poly [adenosine-5'-diphosphate (ADP) -ribose] polymerase) and thereby preventing single-strand break repair (Benafif S et al., Onco. Targets Ther. (2015) 8, 519-528) (Fong PC et al., N. Engl. J. Med. (2009) 361, 123-134) (Gelmon KA et al., Lancet Oncol. (2011) 12, 852-861). PARP includes multiple subtypes, but the PARP inhibitor in the present invention preferably inhibits PARP-1 and PARP-2. PARP inhibitors include, but are not limited to, olaparib (Menear KA et al., J. Med. Chem. (2008) 51, 6581-6591), rucaparib (Gillmore AT et al., Org. Process Res. Dev. (2012) 16, 1897-1904), niraparib (Jones P et al., J. Med. Chem. (2009) 52, 7170-7185), talazoparib (Shen Y et al., Clin. Cancer Res. (2013) 19 (18), 5003-5015), veliparib, pamiparib and fluzoparib, and pharmacologically acceptable salts thereof. Olaparib, rucaparib, niraparib, talazoparib and veliparib, and pharmacologically acceptable salts thereof can be preferably exemplified.

[0371] In this specification, the term "immune checkpoint inhibitor" is used to refer to an agent that inhibits the immunosuppressive system to activate tumor immunity. Immune checkpoint inhibitors include, but are not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies. Anti-PD-1 antibodies and anti-PD-L1 antibodies can be preferably exemplified.

[0372] In the present specification, the term "anti-PD-1 antibody" is used to refer to an antibody that specifically binds to PD-1 (programmed cell death-1; CD279; PDCD1), or a functional fragment of the antibody, wherein the antibody has the activity of reducing, inhibiting and / or interfering with signal transduction caused by the interaction between PD-1 and PD-L1 or PD-L2 as a binding partner. Anti-PD-1 antibodies include, but are not limited to, nivolumab (International Publication No. WO 2006 / 121168, etc.), pembrolizumab (International Publication No. WO 2008 / 156712, etc.), tislelizumab, sintilimab, spartalizumab and cemiplimab.

[0373] In the present specification, the term "anti-PD-L1 antibody" is used to mean an antibody that specifically binds to PD-L1 (programmed cell death ligand 1; CD274; B7-H1), or a functional fragment of the antibody, wherein the antibody has the activity of reducing, inhibiting and / or interfering with signal transduction caused by the interaction between PD-L1 and PD-1 or B7.1 (CD80) as a binding partner. Anti-PD-L1 antibodies include, but are not limited to, atezolizumab (International Publication No. WO 2010 / 077634, etc.), durvalumab (International Publication No. WO 2011 / 066389, etc.) and avelumab (International Publication No. WO 2013 / 079174, etc.).

[0374] In the present specification, the term "anti-CTLA-4 antibody" is used to refer to an antibody that specifically binds to CTLA-4 (cytotoxic T-lymphocyte-associated protein 4; CD152), or a functional fragment of the antibody, wherein the antibody has the activity of reducing, inhibiting and / or interfering with signal transduction caused by the interaction between CTLA-4 and B7.1 (CD80) or B7.2 (CD86) as a binding partner. Anti-CTLA-4 antibodies include, but are not limited to, ipilimumab (International Publication No. WO2001 / 014424, etc.) and tremelimumab (International Publication No. WO2000 / 037504, etc.).

[0375] In the present specification, the term "angiogenesis inhibitor" is used to mean an agent that directly or indirectly inhibits the formation and / or growth of new blood vessels regardless of the mechanism. VEGF (vascular endothelial growth factor) inhibitors can be preferably exemplified.

[0376] In this specification, the term "VEGF inhibitor" is used to refer to an agent that inhibits the interaction between VEGF and VEGF receptor. VEGF inhibitors include, but are not limited to, anti-VEGF antibodies, anti-VEGF receptor antibodies, fusion proteins comprising the extracellular domain of VEGF receptors, and multispecific antibodies with binding specificity to VEGF.

[0377] In this specification, the term "anti-VEGF antibody" is used to refer to an antibody that specifically binds to VEGF, or a functional fragment of the antibody. Anti-VEGF antibodies include, but are not limited to, bevacizumab and sevacizumab. Bevacizumab can be preferably exemplified.

[0378] In this specification, the term "anti-VEGF receptor antibody" is used to refer to an antibody that specifically binds to a VEGF receptor, or a functional fragment of the antibody. Anti-VEGF receptor antibodies include, but are not limited to, ramucirumab.

[0379] In this specification, the term "fusion protein comprising the extracellular domain of VEGF receptor" is used to refer to a fusion protein comprising a binding domain to VEGF, wherein the binding domain is derived from the extracellular domain of VEGF receptor. Fusion proteins comprising the extracellular domain of VEGF receptor include but are not limited to: aflibercept.

[0380] In the present specification, the term "multispecific antibody having binding specificity for VEGF" is used to mean an antibody comprising binding specificities for at least two different sites, one binding specificity for VEGF and another or other binding specificities for any other antigen. Multispecific antibodies with binding specificity for VEGF include, but are not limited to, ivonescimab (Esfandiari et al., Nat. Rev. Drug Discov. (2022) 21(6):411-412), CTX-009 (also known as ABL-001, Xu et al., Cancer Lett. (2022) 538:215699), BI836880 (Clin. Exp. Metastasis (2020) 37(6):637-648), navicixizumab (Esfandiari et al., Nat. Rev. Drug Discov. (2022) 21(6):411-412), and vanucizumab (Xu et al., Cancer Lett. (2022) 538:215699).

[0381] In the present specification, the term "VEGFR-TKI" is used to mean an agent that inhibits the tyrosine kinase of vascular endothelial growth factor receptor (VEGFR). VEGFR-TKI may have an effect of inhibiting kinases other than VEGFR tyrosine kinase. VEGFR-TKIs include, but are not limited to, regorafenib, sorafenib, vandetanib (U.S. Pat. No. 7,173,038), sunitinib (U.S. Pat. No. 6,573,293), axitinib (U.S. Pat. No. 6,534,524), pazopanib (U.S. Pat. No. 7,105,530), lenvatinib (U.S. Pat. No. 7,253,286), nintedanib (hereinafter, also referred to as "BIBF1120") (U.S. Pat. No. 6,762,180), cabozantinib (U.S. Pat. No. 7,579,473), tivozanib (International Publication No. WO 2002 / 088110), brivanib (International Publication No. WO2004 / 009784), linifanib (International Publication No. WO 2014 / 022975), lucitanib (International Publication No. WO 2008 / 112408), ilorasertib and ENMD-2076, and pharmacologically acceptable salts thereof.

[0382] In this specification, the term "cancer recurrence" is used to mean that cancer reappears in the same location as the primary tumor or in another location in the body after a period of time during which the cancer cannot be detected. The term is defined based on "recurrence" in the following references. NCI Dictionary, "Recurrence", NCI Cancer Terms Dictionary (NCI Dictionary of Cancer Terms) [online]. National Cancer Institute (National Cancer Institute) [retrieved on 2022-09-06]. From<cancer.gov / publications / dictionaries / cancer-terms / def / recurrence> Retrieve.

[0383] In this specification, the term "chemotherapy regimen" is used to refer to a chemotherapy treatment plan, which defines one or more drugs, dosages, frequencies, etc.

[0384] In this specification, the term "complete response (CR)" is used to mean that all signs of cancer disappear in response to treatment. "Complete response (CR)" does not always mean that the cancer has been cured. The term can also be expressed as "complete remission". The term is defined based on "complete remission" in the following references. NCI Dictionary, "Complete Remission", NCI Cancer Terminology Dictionary [Online]. National Cancer Institute of the United States [Retrieved on 2022-09-06]. From<cancer.gov / publications / dictionaries / cancer-terms / def / complete-response> Retrieve.

[0385] In this specification, the term "partial response (PR)" is used to mean that the size of a tumor or the extent of cancer in the body is reduced in response to treatment. The term may also be expressed as "partial remission". The term is defined based on "partial remission" in the following references. NCI Dictionary, "Partial Remission", NCI Cancer Terms Dictionary [Online]. National Cancer Institute of the United States [Retrieved on 2022-09-06]. From<cancer.gov / publications / dictionaries / cancer-terms / def / partial-response> Retrieve.

[0386] In this specification, the term "stable disease (SD)" is used to mean that the extent or severity of cancer is neither decreasing nor increasing. The term is defined based on "stable disease" in the following references. NCI Dictionary, "Stable Disease", NCI Cancer Dictionary [Online]. National Cancer Institute [Retrieved on 2022-09-06]. From<cancer.gov / publications / dictionaries / cancer-terms / def / stable-disease> Retrieve.

[0387] In this specification, the term "progressive disease" or "PD" is used to refer to a cancer that is growing, spreading, or getting worse. The term is defined based on the following references for "progressive disease". NCI Dictionary, "Progressive Disease", NCI Cancer Dictionary [Online]. National Cancer Institute [retrieved on 2023-04-02]. From<cancer.gov / publications / dictionaries / cancer-terms / def / progressive-disease> Retrieve.

[0388] In this specification, the term "objective response rate" or "ORR" is used to refer to the percentage of people in a study or treatment group who have a partial response (PR) or complete response (CR) to treatment within a certain period of time. The term is defined based on "ORR" in the following references. NCI Dictionary, "ORR", NCI Cancer Terms Dictionary [Online]. National Cancer Institute of the United States [Retrieved on 2023-04-02]. From<cancer.gov / publications / dictionaries / cancer-terms / def / orr> Retrieve.

[0389] In this specification, the term "progression free survival" or "PFS" is used to refer to the length of time a patient survives the disease without the disease getting worse during and after treatment of a disease such as cancer. The term is defined based on "PFS" in the following references. NCI Dictionary, "PFS", NCI Cancer Terms Dictionary [Online]. National Cancer Institute [Retrieved on 2023-04-02]. From<cancer.gov / publications / dictionaries / cancer-terms / def / pfs> Retrieve.

[0390] In this specification, the term "maintenance therapy" is used to refer to treatment given after the cancer has gone away after initial therapy to help prevent the cancer from coming back. The term is defined based on the following references for "maintenance therapy". NCI Dictionary, "Maintenance Therapy", NCI Dictionary of Cancer Terms [Online]. National Cancer Institute [Retrieved on 2023-04-10]. From<cancer.gov / publications / dictionaries / cancer-terms / def / maintenance-therapy> Retrieve.

[0391] In this specification, the term "adjuvant therapy" is used to mean additional cancer treatment given after primary treatment to reduce the risk that the cancer will reappear. The term is defined based on "adjuvant therapy" in the following references. NCI Dictionary, "Adjuvant Therapy", NCI Cancer Terms Dictionary [Online]. National Cancer Institute [Retrieved on 2023-04-10]. From<cancer.gov / publications / dictionaries / cancer-terms / def / adjuvant-therapy> Retrieve.

[0392] In this specification, "adjuvant cancer therapy" is used to mean a treatment given as a first step to shrink a tumor before a primary treatment such as surgery is given. The term is defined based on "adjuvant cancer therapy" in the following references. NCI Dictionary, "Adjuvant cancer therapy", NCI Cancer Terms Dictionary [online]. National Cancer Institute [retrieved on 2023-04-10]. From<cancer.gov / publications / dictionaries / cancer-terms / def / neoadjuvant-therapy> Retrieve.

[0393] As amino acid substitutions in this specification, conservative amino acid substitutions are preferred. Conservative amino acid substitutions refer to substitutions that occur within a group of amino acids related to the amino acid side chain. Preferred amino acid groups are as follows: acidic group (aspartic acid and glutamic acid); basic group (lysine, arginine and histidine); non-polar group (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine and tryptophan); and non-charged polar family (glycine, asparagine, glutamine, cysteine, serine, threonine and tyrosine). More preferred amino acid groups are as follows: aliphatic hydroxyl group (serine and threonine); amide-containing group (asparagine and glutamine); aliphatic group (alanine, valine, leucine and isoleucine); and aromatic group (phenylalanine, tryptophan and tyrosine). Such amino acid substitutions are preferably carried out within the range that does not damage the properties of the substance having the original amino acid sequence.

[0394] Throughout the specification, when compositions are described as having, including, or comprising specific components, or when processes and methods are described as having, including, or comprising specific steps, it is contemplated that there are additional compositions of the disclosure consisting essentially of, or consisting of, the recited components, and that there are processes and methods according to the disclosure consisting essentially of, or consisting of, the recited process steps.

[0395] Generally, compositions specifying percentages are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, the preceding definition for the variable controls.

[0396] 1.CDH6 Cadherins are glycoproteins present on the cell membrane surface and function as cell-cell adhesion molecules through calcium ion-dependent binding of their N-terminal extracellular domains, or as signaling molecules responsible for cell-cell interactions. Classical cadherins are in the cadherin superfamily and are single-pass transmembrane proteins consisting of five extracellular domains (EC domains), a transmembrane region, and an intracellular domain.

[0397] CDH6 (cadherin-6) is a single transmembrane protein consisting of 790 amino acids, which is classified as the type II cadherin family, and the protein has an N-terminal extracellular and C-terminal intracellular domains. The human CDH6 gene was first cloned in 1995 (non-patent literature 1), and its sequence can be referenced to, for example, accession numbers NM_004932 and NP_004923 (NCBI).

[0398] The CDH6 protein used in the present disclosure can be directly purified from a cell expressing CDH6 of a human or non-human mammal (e.g., rat, mouse or monkey), and then can be used, or a cell membrane fraction of the above-mentioned cell can be prepared and can be used as a CDH6 protein. On the other hand, CDH6 can also be obtained by in vitro synthesis or by allowing a host cell to produce CDH6 by genetic manipulation. According to this genetic manipulation, CDH6 protein can be obtained, specifically, by incorporating CDH6 cDNA into a vector capable of expressing CDH6 cDNA, and then synthesizing CDH6 in a solution containing enzymes, substrates and energy materials necessary for transcription and translation, or by transforming host cells of other prokaryotes or eukaryotes, so as to allow them to express CDH6. Similarly, cells expressing CDH6 based on the above-mentioned genetic manipulation, or cell lines expressing CDH6 can be used to present CDH6 protein. On the other hand, an expression vector into which CDH6 cDNA has been incorporated can be directly administered to an animal to be immunized, and CDH6 can be expressed in the animal so immunized.

[0399] In addition, the term "CDH6" also includes proteins that consist of an amino acid sequence containing one or more amino acids substituted, deleted and / or added in the amino acid sequence of the above-mentioned CDH6 and have biological activities equivalent to those of the CDH6 protein.

[0400] The human CDH6 protein has the amino acid sequence shown in SEQ ID NO: 1. The extracellular region of the human CDH6 protein is composed of the following: an extracellular domain 1 having an amino acid sequence of positions 54 to 159 in the amino acid sequence shown in SEQ ID NO: 1 (also referred to as EC1 in this specification), an extracellular domain 2 having an amino acid sequence of positions 160 to 268 in the amino acid sequence shown in SEQ ID NO: 1 (also referred to as EC2 in this specification), an extracellular domain 3 having an amino acid sequence of positions 269 to 383 in the amino acid sequence shown in SEQ ID NO: 1 (also referred to as EC3 in this specification), an extracellular domain 4 having an amino acid sequence of positions 384 to 486 in the amino acid sequence shown in SEQ ID NO: 1 (also referred to as EC4 in this specification), and an extracellular domain 5 having an amino acid sequence of positions 487 to 608 in the amino acid sequence shown in SEQ ID NO: 1 (also referred to as EC5 in this specification). The amino acid sequences of EC1 to EC5 are shown in SEQ ID NOs: 2 to 6, respectively (Table 1).

[0401] 2. Generation of Anti-CDH6 Antibodies An example of an anti-CDH6 antibody of the present disclosure may include an anti-CDH6 antibody that recognizes an amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 4 and has internalization activity. An example of an anti-CDH6 antibody of the present disclosure may include an anti-CDH6 antibody that specifically recognizes an amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 4 and has internalization activity. An example of an anti-CDH6 antibody of the present disclosure may include an anti-CDH6 antibody that recognizes an amino acid sequence consisting of the amino acid sequence shown in SEQ ID NO: 4 and has internalization activity. An example of an anti-CDH6 antibody of the present disclosure may include an anti-CDH6 antibody that specifically recognizes an amino acid sequence consisting of the amino acid sequence shown in SEQ ID NO: 4 and has internalization activity. The phrase "specifically recognizes an amino acid sequence comprising the amino acid sequence shown in SEQ ID NO: 4" or "specifically recognizes an EC3 domain" when applied to an antibody is used to mean that the antibody strongly recognizes or strongly binds to the EC3 domain of CDH6 compared to other extracellular domains of CDH6.

[0402] The anti-CDH6 antibodies of the present disclosure may be derived from any species. Preferred examples of the species may include humans, monkeys, rats, mice and rabbits. When the anti-CDH6 antibodies of the present disclosure are derived from species other than humans, the anti-CDH6 antibodies are preferably chimeric or humanized by well-known techniques. The antibodies of the present disclosure may be polyclonal antibodies, or may be monoclonal antibodies, and preferably monoclonal antibodies.

[0403] The anti-CDH6 antibodies of the present disclosure are antibodies that can target tumor cells. Specifically, the anti-CDH6 antibodies of the present disclosure have the property of being able to recognize tumor cells, the property of being able to bind to tumor cells, and / or the property of being internalized into tumor cells through cell uptake, etc. Therefore, the anti-CDH6 antibodies of the present disclosure can be conjugated to a compound having anti-tumor activity via a linker to prepare an antibody-drug conjugate.

[0404] The binding activity of the antibody to tumor cells can be confirmed by flow cytometry. The uptake of the antibody into tumor cells can be confirmed by: (1) an assay of the antibody showing cellular uptake under a fluorescence microscope using a second antibody (fluorescently labeled) that binds to the antibody (Cell Death and Differentiation, 2008, 15, 751-761), (2) an assay of the amount of fluorescence measured by cellular uptake using a second antibody (fluorescently labeled) that binds to the antibody (Molecular Biology of the Cell Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay using an immunotoxin that binds to the antibody, wherein the toxin is released upon cellular uptake to inhibit cell growth (Bio Techniques 28: 162-165, January 2000). Recombinant conjugated proteins of the catalytic region of diphtheria toxin and G protein can be used as immunotoxins.

[0405] In the present specification, the term "high internalization ability" is used to mean that the survival rate of CDH6-expressing cells to which the above-mentioned antibodies and saponin-labeled anti-rat IgG antibodies have been administered (which is indicated by the ratio relative to the survival rate of cells without antibody addition defined as 100%) is preferably 70% or less, and more preferably 60% or less.

[0406] The anti-tumor antibody-drug conjugates of the present disclosure contain conjugated compounds that exert anti-tumor effects. Therefore, preferably but not necessarily, the antibody itself should have an anti-tumor effect. In order to specifically and / or selectively exert the cytotoxicity of the anti-tumor compound in tumor cells, it is important and preferred that the antibody should have the property of being internalized and transferred into tumor cells.

[0407] Anti-CDH6 antibodies can be obtained by immunizing an animal with a polypeptide serving as an antigen by a method commonly performed in the art, and then collecting and purifying antibodies produced in the living animal. It is preferred to use CDH6 that retains a three-dimensional structure as an antigen. Examples of this method may include DNA immunization methods.

[0408] The source of the antigen is not limited to humans, and therefore, an antigen derived from a non-human animal such as a mouse or rat can also be used to immunize an animal. In the case, an antibody suitable for a human disease can be selected by examining the cross-reactivity of the obtained antibody binding to a heterologous antigen with a human antigen.

[0409] Furthermore, antibody-producing cells that produce antibodies against an antigen can be fused with myeloma cells according to known methods (e.g., Kohler and Milstein, Nature (1975) 256, 495-497; and Kennet, R., ed., Monoclonal Antibodies, 365-367, Plenum Press, NY (1980)) to establish hybridomas to obtain monoclonal antibodies.

[0410] Hereinafter, the method for obtaining an antibody against CDH6 will be described in detail.

[0411] (1) Preparation of Antigen Antigens can be obtained by allowing host cells to produce genes encoding antigenic proteins according to genetic manipulation. Specifically, a vector capable of expressing the antigenic gene is produced, and then the vector is introduced into a host cell so that the gene is expressed therein, and thereafter, the expressed antigen can be purified. Antibodies can also be obtained by using antigen-expressing cells based on the above-mentioned genetic manipulation or a cell line immunizing an animal expressing the antigen.

[0412] On the other hand, without using an antigen protein, antibodies can also be obtained by incorporating the cDNA of the antigen protein into an expression vector, then administering the expression vector to an animal to be immunized, and expressing the antigen protein in the animal thus immunized, thereby producing antibodies against the antigen protein therein.

[0413] (2) Production of anti-CDH6 monoclonal antibodies The anti-CDH6 antibody used in the present disclosure is not particularly limited. For example, the antibody detailed by the amino acid sequence shown in the sequence table of the present application can be appropriately used. The anti-CDH6 antibody used in the present disclosure is desirably an antibody having the following properties: (1) Antibodies having the following properties: (a) specifically binds to CDH6, and (b) having an activity of binding to CDH6 and being internalized into cells expressing CDH6; (2) The antibody according to (1) above, wherein the CDH6 is human CDH6; or (3) The antibody according to (1) or (2) above, wherein the antibody specifically recognizes EC3 of human CDH6 and has internalization activity.

[0414] The method for obtaining the antibody against CDH6 of the present disclosure is not particularly limited as long as the anti-CDH6 antibody can be obtained. It is preferred to use CDH6 that retains its conformation as an antigen.

[0415] A preferred example of the method for obtaining antibodies may include DNA immunization. DNA immunization is a method comprising transfecting an animal (e.g., mouse or rat) individual with an antigen expression plasmid, and then expressing the antigen in the individual to induce immunity to the antigen. Transfection methods include methods of injecting plasmids directly into muscles, methods of injecting transfection reagents such as liposomes or polyethyleneimine into veins, methods using viral vectors, methods of injecting gold particles attached to plasmids using a gene gun, and hydrodynamic methods of rapidly injecting a large amount of plasmid solutions into veins. Regarding the transfection method of injecting an expression plasmid into muscle, as a method for increasing the expression level, a technique called in vivo electroporation is known, which comprises applying electroporation to the intramuscular injection site of the plasmid (Aihara H, Miyazaki J. Nat Biotechnol. 1998 Sep; 16(9): 867-70 or Mir LM, Bureau MF, Gehl J, Rangara R, Rouy D, Caillaud JM, Delaere P, Branellec D, Schwartz B, Scherman D. Proc Natl Acad Sci USA. 1999 Apr 13; 96(8): 4262-7). The method further improves the expression level by treating the muscle with hyaluronidase before intramuscular injection of the plasmid (McMahon JM1, Signori E, Wells KE, Fazio VM, Wells DJ., Gene Ther. 2001 August; 8(16): 1264-70). In addition, the production of hybridomas can be carried out by known methods, and can also be carried out using, for example, the Hybrimune hybridoma production system (Cyto Pulse Sciences, Inc.).

[0416] A specific example of obtaining a monoclonal antibody may include the following procedures: (a) CDH6 cDNA is incorporated into an expression vector (e.g., pcDNA3.1; Thermo Fisher Scientific Inc.), and the vector is directly administered to an animal to be immunized (e.g., a rat or a mouse) by a method such as electroporation or a gene gun, so that CDH6 is expressed in the animal, and an immune response can be induced. If necessary to increase the antibody titer, the vector administration by electroporation or the like can be performed once or multiple times, preferably multiple times; (b) collecting tissues (e.g., lymph nodes) containing antibody-producing cells from the above-mentioned animal in which an immune response has been induced; (c) preparing myeloma cells (hereinafter referred to as "myeloma") (e.g., mouse myeloma SP2 / 0-ag14 cells); (d) cell fusion between antibody-producing cells and myeloma cells; (e) selecting a group of hybridomas that produce antibodies of interest; (f) division into single-cell clones (clones); (g) optionally, culturing the hybridoma for mass production of monoclonal antibodies, or breeding animals inoculated with the hybridoma; and / or (h) studying the physiological activity (internalization activity) and binding specificity of the monoclonal antibody thus produced, or examining the properties of the antibody as a labeling agent.

[0417] Examples of methods for measuring the antibody titer used herein may include, but are not limited to, flow cytometry and cell ELISA.

[0418] Examples of the hybridoma strains thus established may include anti-CDH6 antibody-producing hybridomas rG019, rG055, rG056, and rG061. Note that in the present specification, the antibody produced by the anti-CDH6 antibody-producing hybridoma rG019 is referred to as "rG019 antibody" or simply "rG019", the antibody produced by the hybridoma rG055 is referred to as "rG055 antibody" or simply "rG055", the antibody produced by the hybridoma rG056 is referred to as "rG056 antibody" or simply "rG056", and the antibody produced by the hybridoma rG061 is referred to as "rG061 antibody" or simply "rG061".

[0419] The light chain variable region of the rG019 antibody consists of the amino acid sequence shown in SEQ ID NO: 10. The amino acid sequence of the light chain variable region of the rG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 11. The light chain variable region of the rG019 antibody has CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14. The heavy chain variable region of the rG019 antibody consists of the amino acid sequence shown in SEQ ID NO: 15. The amino acid sequence of the heavy chain variable region of the rG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 16. The heavy chain variable region of the rG019 antibody has CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 18, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 19. The sequence of the rG019 antibody is shown in Table 1.

[0420] The light chain variable region of the rG055 antibody consists of the amino acid sequence shown in SEQ ID NO: 20. The amino acid sequence of the light chain variable region of the rG055 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 21. The light chain variable region of the rG055 antibody has CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 22, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 23, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 24. The heavy chain variable region of the rG055 antibody consists of the amino acid sequence shown in SEQ ID NO: 25. The amino acid sequence of the heavy chain variable region of the rG055 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 26. The heavy chain variable region of the rG055 antibody has CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 27, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 28, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 29. The sequence of the rG055 antibody is shown in Table 1.

[0421] The light chain variable region of the rG056 antibody consists of the amino acid sequence shown in SEQ ID NO: 30. The amino acid sequence of the light chain variable region of the rG056 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 31. The light chain variable region of the rG056 antibody has CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 32, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 33, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 34. The heavy chain variable region of the rG056 antibody consists of the amino acid sequence shown in SEQ ID NO: 35. The amino acid sequence of the heavy chain variable region of the rG056 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 36. The heavy chain variable region of the rG056 antibody has CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 37, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 38, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 39. The sequence of the rG056 antibody is shown in Table 1.

[0422] The light chain variable region of the rG061 antibody consists of the amino acid sequence shown in SEQ ID NO: 40. The amino acid sequence of the light chain variable region of the rG061 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 41. The light chain variable region of the rG061 antibody has CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 42, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 43, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 44. The heavy chain variable region of the rG061 antibody consists of the amino acid sequence shown in SEQ ID NO: 45. The amino acid sequence of the heavy chain variable region of the rG061 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 46. The heavy chain variable region of the rG061 antibody has CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 47, CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 48, and CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 49. The sequence of the rG061 antibody is shown in Table 1.

[0423] Furthermore, in the case where steps (a) to (h) in the above-mentioned "2. Production of anti-CDH6 antibodies" are performed again to independently obtain monoclonal antibodies separately, and also in the case where monoclonal antibodies are obtained separately by other methods, antibodies having internalization activity equivalent to that of rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody can be obtained. An example of such an antibody may include an antibody that binds to the same epitope as the epitope to which rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody binds. If the newly prepared monoclonal antibody binds to a portion of the peptide or a portion of the three-dimensional structure to which rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody binds, it can be determined that the monoclonal antibody binds to the same epitope as the epitope to which rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody binds. Furthermore, by confirming that the monoclonal antibody competes with the rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody in the binding of the antibody to CDH6 (i.e., the monoclonal antibody interferes with the binding of the rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody to CDH6), it can be determined that the monoclonal antibody binds to the same epitope as the epitope to which the anti-CDH6 antibody binds, even if the specific sequence or structure of the epitope has not yet been determined. When it is confirmed that the monoclonal antibody binds to the same epitope as the epitope to which the rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody binds, it is then strongly expected that the monoclonal antibody should have an antigen-binding ability, biological activity, and / or internalization activity equivalent to those of the rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody.

[0424] (3) Other antibodies The antibodies of the present disclosure also include genetically recombinant antibodies that have been artificially modified for the purpose of reducing heterologous antigenicity to humans, such as chimeric antibodies, humanized antibodies, and human antibodies, as well as the above-mentioned monoclonal antibodies against CDH6. These antibodies can be produced by known methods.

[0425] Examples of chimeric antibodies may include antibodies in which the variable region and the constant region are heterologous to each other, such as chimeric antibodies formed by conjugating the variable region of a mouse- or rat-derived antibody to a human-derived constant region (see Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0426] Examples of chimeric antibodies derived from rat anti-human CDH6 antibodies include antibodies composed of a light chain comprising the light chain variable region of each rat anti-human CDH6 antibody described in the present specification (e.g., rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody) and a human-derived constant region, and a heavy chain comprising its heavy chain variable region and a human-derived constant region.

[0427] Other examples of chimeric antibodies derived from rat anti-human CDH6 antibodies include antibodies composed of: a light chain comprising a light chain variable region in which one to several residues, 1 to 3 residues, 1 or 2 residues, preferably 1 residue of amino acids in the light chain variable region of each rat anti-human CDH6 antibody described in the specification (e.g., rG019 antibody, rG055 antibody, rG056 antibody or rG061 antibody) are substituted with other amino acid residues, and a heavy chain comprising a heavy chain variable region in which one to several residues, 1 to 3 residues, 1 or 2 residues, preferably 1 residue of amino acids in its heavy chain variable region are substituted with other amino acid residues. The antibody may have any given human-derived constant region.

[0428] Other examples of chimeric antibodies derived from rat anti-human CDH6 antibodies include antibodies composed of: a light chain comprising a light chain variable region in which 1 or 2 residues, preferably 1 residue, of an amino acid in any 1 to 3 CDRs of the light chain variable region of each rat anti-human CDH6 antibody described in the present specification (e.g., rG019 antibody, rG055 antibody, rG056 antibody, or rG061 antibody) are substituted with other amino acid residues, and a heavy chain comprising a heavy chain variable region in which 1 or 2 residues, preferably 1 residue, of an amino acid in any 1 to 3 CDRs of the heavy chain variable region thereof are substituted with other amino acid residues. The antibody may have any given human-derived constant region.

[0429] Examples of chimeric antibodies derived from the rG019 antibody include antibodies consisting of a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10 and a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 15. The antibody may have any given human-derived constant region.

[0430] Other examples of chimeric antibodies derived from rG019 antibody include antibodies consisting of: a light chain comprising a light chain variable region having one to several residues, 1 to 3 residues, 1 or 2 residues, preferably 1 residue of amino acids in the light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10 substituted with other amino acid residues, and a heavy chain comprising a heavy chain variable region having one to several residues, 1 to 3 residues, 1 or 2 residues, preferably 1 residue of amino acids in the heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 15 substituted with other amino acid residues. The antibody may have any given human-derived constant region.

[0431] Other examples of chimeric antibodies derived from rG019 antibody include antibodies consisting of: a light chain comprising a light chain variable region in which 1 or 2 residues (preferably 1 residue) of an amino acid in any 1 to 3 CDRs of a light chain variable region consisting of an amino acid sequence shown in SEQ ID NO: 10 are substituted with other amino acid residues, and a heavy chain comprising a heavy chain variable region in which 1 or 2 residues (preferably 1 residue) of an amino acid in any 1 to 3 CDRs of a heavy chain variable region consisting of an amino acid sequence shown in SEQ ID NO: 15 are substituted with other amino acid residues. The antibody may have any given human-derived constant region.

[0432] Other examples of chimeric antibodies derived from rG019 antibody include antibodies consisting of a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 10 and a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 58. The antibody may have any given human-derived constant region. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which a cysteine ​​residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 15 is substituted with a proline residue.

[0433] Specific examples of chimeric antibodies derived from rG019 antibodies include antibodies consisting of a light chain and a heavy chain, wherein the light chain consists of the light chain full-length amino acid sequence shown in SEQ ID NO: 53, and the heavy chain consists of the heavy chain full-length amino acid sequence shown in SEQ ID NO: 56. In the present specification, the chimeric anti-human CDH6 antibody is referred to as "chimeric G019 antibody", "chG019 antibody" or "chG019". The light chain full-length amino acid sequence of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 54, and the heavy chain full-length amino acid sequence of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 57.

[0434] The amino acid sequence of the light chain variable region of the chG019 antibody is identical to that of the rG019 antibody and consists of the amino acid sequence shown in SEQ ID NO: 10. The light chain of the chG019 antibody has CDRL1 consisting of the amino acid sequence shown in SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence shown in SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence shown in SEQ ID NO: 14, which are identical to the light chain CDRL1, CDRL2, and CDRL3 of rG019, respectively. The amino acid sequence of the light chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 55.

[0435] The amino acid sequence of the heavy chain variable region of the chG019 antibody consists of the amino acid sequence shown in SEQ ID NO: 58. The heavy chain of the chG019 antibody has a CDRH1 consisting of the amino acid sequence shown in SEQ ID NO: 17, a CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60, and a CDRH3 consisting of the amino acid sequence shown in SEQ ID NO: 19. The amino acid sequence shown in SEQ ID NO: 58 is a sequence in which the cysteine ​​residue in CDRH2 in the amino acid sequence shown in SEQ ID NO: 15 is substituted with a proline residue. The CDRH2 consisting of the amino acid sequence shown in SEQ ID NO: 60 is a sequence in which the cysteine ​​residue in the rG019 CDRH2 shown in SEQ ID NO: 18 is substituted with a proline residue. The amino acid sequence of the heavy chain variable region of the chG019 antibody is encoded by the nucleotide sequence shown in SEQ ID NO: 59.

[0436] The sequence of the chG019 antibody is shown in Table 1.

[0437] Examples of chimeric antibodies derived from rat anti-human CDH6 antibody rG055 antibody include chimeric antibodies consisting of a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 20 and a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 25. The antibody may have any given human-derived constant region.

[0438] Examples of chimeric antibodies derived from rat anti-human CDH6 antibody rG056 antibody include chimeric antibodies consisting of a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 30 and a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 35. The antibody may have any given human-derived constant region.

[0439] Examples of chimeric antibodies derived from rat anti-human CDH6 antibody rG061 antibody include chimeric antibodies consisting of a light chain comprising a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 40 and a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 45. The antibody may have any given human-derived constant region.

[0440] Examples of humanized antibodies may include antibodies formed by incorporating only complementarity determining regions (CDRs) into a human-derived antibody (see Nature (1986) 321, p. 522-525), antibodies formed by incorporating amino acid residues from some frameworks as well as CDR sequences into a human antibody according to a CDR grafting method (International Publication No. WO90 / 07861), and antibodies formed by modifying the amino acid sequences of some CDRs while maintaining antigen-binding ability.

[0441] In the present specification, the humanized antibody derived from rG019 antibody, rG055 antibody, rG056 antibody, rG061 antibody or chG019 antibody is not limited to a specific humanized antibody, as long as the humanized antibody retains all 6 CDR sequences unique to rG019 antibody, rG055 antibody, rG056 antibody, rG061 antibody or chG019 antibody and has internalization activity. The amino acid sequence of some CDRs of the humanized antibody may be further modified as long as it has internalization activity.

[0442] Specific examples of humanized antibodies of the chG019 antibody may include any given combination of the following: a light chain comprising a light chain variable region consisting of any one amino acid sequence selected from the group consisting of: (1) an amino acid sequence shown in SEQ ID NO: 63 or 67, (2) an amino acid sequence having at least 95% or higher identity with the above amino acid sequence (1) (preferably an amino acid sequence having at least 95% or higher sequence identity with the sequence of the framework region excluding each CDR sequence), and (3) an amino acid sequence comprising a deletion, substitution or addition of one or several amino acids in the above amino acid sequence (1); and a heavy chain comprising a heavy chain variable region consisting of any one amino acid sequence selected from the group consisting of: (4) an amino acid sequence shown in SEQ ID NO: 71, 75 or 79, (5) an amino acid sequence having at least 95% or higher identity with the above amino acid sequence (4) (preferably an amino acid sequence having at least 95% or higher sequence identity with the sequence of the framework region excluding each CDR sequence), and (6) an amino acid sequence comprising a deletion, substitution or addition of one or several amino acids in the above amino acid sequence (4).

[0443] On the other hand, antibodies having a humanized heavy chain or light chain and the other chain derived from a rat antibody or a chimeric antibody can also be used. Examples of such antibodies may include any given combination of the following: a light chain comprising a light chain variable region consisting of any one amino acid sequence selected from the group consisting of: (1) an amino acid sequence shown in SEQ ID NO: 63 or 67, (2) an amino acid sequence having at least 95% or higher identity with the above amino acid sequence (1) (preferably an amino acid sequence having at least 95% or higher sequence identity with the sequence of the framework region excluding each CDR sequence), and (3) an amino acid sequence comprising a deletion, substitution or addition of one or several amino acids in the above amino acid sequence (1); and a heavy chain comprising a heavy chain variable region consisting of any one amino acid sequence selected from the group consisting of: (4) an amino acid sequence shown in SEQ ID NO: 15, 25, 35, 45 or 58, (5) an amino acid sequence having at least 95% or higher identity with the above amino acid sequence (4) (preferably an amino acid sequence having at least 95% or higher sequence identity with the sequence of the framework region excluding each CDR sequence), and (6) an amino acid sequence comprising a deletion, substitution or addition of one or several amino acids in the above amino acid sequence (4). Other examples of such antibodies may include any given combination of the following: a light chain comprising a light chain variable region consisting of any one of the following amino acid sequences selected from the group consisting of: (1) an amino acid sequence shown in SEQ ID NO: 10, 20, 30 or 40, (2) an amino acid sequence having at least 95% or higher identity with the above amino acid sequence (1) (preferably an amino acid sequence having at least 95% or higher sequence identity with the sequence of the framework region excluding each CDR sequence), and (3) an amino acid sequence comprising a deletion, substitution or addition of one or several amino acids in the above amino acid sequence (1); and a heavy chain comprising a heavy chain variable region consisting of any one of the following amino acid sequences selected from the group consisting of: (4) an amino acid sequence shown in SEQ ID NO: 71, 75 or 79, (5) an amino acid sequence having at least 95% or higher identity with the above amino acid sequence (4) (preferably an amino acid sequence having at least 95% or higher sequence identity with the sequence of the framework region excluding each CDR sequence), and (6) an amino acid sequence comprising a deletion, substitution or addition of one or several amino acids in the above amino acid sequence (4).

[0444] The amino acid substitutions in this specification are preferably conservative amino acid substitutions. Conservative amino acid substitutions are substitutions that occur within groups of amino acids that are associated with certain amino acid side chains. Preferred amino acid groups are as follows: acidic group = aspartic acid and glutamic acid; basic group = lysine, arginine and histidine; non-polar group = alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine and tryptophan; and non-charged polar family = glycine, asparagine, glutamine, cysteine, serine, threonine and tyrosine. Other preferred amino acid groups are as follows: aliphatic hydroxyl group = serine and threonine; amide-containing group = asparagine and glutamine; aliphatic group = alanine, valine, leucine and isoleucine; and aromatic group = phenylalanine, tryptophan and tyrosine. It is preferred that such amino acid substitutions be made without compromising the properties of the substance having the original amino acid sequence.

[0445] Examples of antibodies having a preferred combination of the above-mentioned light chain and heavy chain include antibodies composed of a light chain having the light chain variable region amino acid sequence shown in SEQ ID NO: 63 (in the present specification, also referred to as hL02 light chain variable region amino acid sequence) or a light chain having the light chain variable region amino acid sequence shown in SEQ ID NO: 67 (in the present specification, also referred to as hL03 light chain variable region amino acid sequence), and a heavy chain having the heavy chain variable region amino acid sequence shown in SEQ ID NO: 71 (in the present specification, also referred to as hH01 heavy chain variable region amino acid sequence), a heavy chain having the heavy chain variable region amino acid sequence shown in SEQ ID NO: 75 (in the present specification, also referred to as hH02 heavy chain variable region amino acid sequence), or a heavy chain having the heavy chain variable region amino acid sequence shown in SEQ ID NO: 79 (in the present specification, also referred to as hH04 heavy chain variable region amino acid sequence). Preferred examples thereof include: an antibody consisting of a light chain having a light chain variable region amino acid sequence as shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence as shown in SEQ ID NO: 71; an antibody consisting of a light chain having a light chain variable region amino acid sequence as shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence as shown in SEQ ID NO: 75; an antibody consisting of a light chain having a light chain variable region amino acid sequence as shown in SEQ ID NO: 63 and a heavy chain having a heavy chain variable region amino acid sequence as shown in SEQ ID NO: 79; an antibody consisting of a light chain having a light chain variable region amino acid sequence as shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence as shown in SEQ ID NO: 71; an antibody consisting of a light chain having a light chain variable region amino acid sequence as shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence as shown in SEQ ID NO: 75; and an antibody consisting of a light chain having a light chain variable region amino acid sequence as shown in SEQ ID NO: 67 and a heavy chain having a heavy chain variable region amino acid sequence as shown in SEQ ID NO: An antibody composed of a heavy chain having the amino acid sequence of the heavy chain variable region shown in NO:79.More preferred examples thereof include: an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO:63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO:71; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO:63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO:75; an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO:63 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO:79; and an antibody consisting of a light chain having a light chain variable region amino acid sequence shown in SEQ ID NO:67 and a heavy chain having a heavy chain variable region amino acid sequence shown in SEQ ID NO:75.

[0446] Other examples of antibodies having the above-mentioned preferred combination of light chains and heavy chains include antibodies consisting of a light chain consisting of the amino acid sequence at positions 21 to 233 in the light chain full-length amino acid sequence shown in SEQ ID NO: 61 (in the present specification, also referred to as hL02 light chain full-length amino acid sequence), or a light chain consisting of the amino acid sequence at positions 21 to 233 in the light chain full-length amino acid sequence shown in SEQ ID NO: 65 (in the present specification, also referred to as hL03 light chain full-length amino acid sequence), and a heavy chain consisting of the amino acid sequence at positions 20 to 471 in the heavy chain full-length amino acid sequence shown in SEQ ID NO: 69 (in the present specification, also referred to as hH01 heavy chain full-length amino acid sequence), a heavy chain consisting of the amino acid sequence at positions 20 to 471 in the heavy chain full-length amino acid sequence shown in SEQ ID NO: 73 (in the present specification, also referred to as hH02 heavy chain full-length amino acid sequence), or a heavy chain consisting of the amino acid sequence at positions 21 to 233 in the light chain full-length amino acid sequence shown in SEQ ID NO: 65 A heavy chain consisting of the amino acid sequence at positions 20 to 471 in the heavy chain full-length amino acid sequence shown in NO: 77 (also referred to as hH04 heavy chain full-length amino acid sequence in the present specification).Preferred examples thereof include: an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain as shown in SEQ ID NO: 61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain as shown in SEQ ID NO: 69; an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain as shown in SEQ ID NO: 61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain as shown in SEQ ID NO: 73; an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain as shown in SEQ ID NO: 61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain as shown in SEQ ID NO: 77; an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain as shown in SEQ ID NO: 61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain as shown in SEQ ID NO: 77 NO:65, and the heavy chain consists of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain shown in SEQ ID NO:65, and the heavy chain consists of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain shown in SEQ ID NO:69; an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain shown in SEQ ID NO:65, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain shown in SEQ ID NO:73; and an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain shown in SEQ ID NO:65, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain shown in SEQ ID NO:77.More preferred examples thereof include: an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 69 (in the present specification, also referred to as “H01L02 antibody” or “H01L02”); an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in the present specification, also referred to as “H02L02 antibody” or “H02L02”); an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (in the present specification, also referred to as “H02L02 antibody” or “H02L02”). The antibody is an antibody consisting of an amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain shown in SEQ ID NO: 61, and the heavy chain consists of an amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 77 (also referred to as "H04L02 antibody" or "H04L02" in the present specification); and an antibody consisting of a light chain and a heavy chain, the light chain consisting of an amino acid sequence at positions 21 to 233 in the full-length amino acid sequence of the light chain shown in SEQ ID NO: 65, and the heavy chain consisting of an amino acid sequence at positions 20 to 471 in the full-length amino acid sequence of the heavy chain shown in SEQ ID NO: 73 (also referred to as "H02L03 antibody" or "H02L03" in the present specification). The sequence of the H01L02 antibody, H02L02 antibody, H02L03 antibody or H04L02 antibody is shown in Table 1.

[0447] By combining sequences showing high identity with the above-mentioned heavy chain amino acid sequence and light chain amino acid sequence, it is possible to select an antibody having biological activity equivalent to each of the above-mentioned antibodies. This identity is generally 80% or more, preferably 90% or more, more preferably 95% or more and most preferably 99% or more. In addition, by combining heavy and light chain amino acid sequences containing substitutions, deletions or additions of one or more amino acid residues in terms of the amino acid sequence of the heavy chain or light chain, it is possible to select an antibody having biological activity equivalent to each of the above-mentioned antibodies.

[0448] The identity between two types of amino acid sequences can be determined by aligning the sequences using the default parameters of Clustal W version 2 (Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ and Higgins DG (2007), "Clustal W and Clustal X version 2.0", Bioinformatics. 23(21):2947-2948).

[0449] It should be noted that, in the hL02 light chain full-length amino acid sequence shown in SEQ ID NO:61, the amino acid sequence consisting of the amino acid residues at positions 1 to 20 is a signal sequence, the amino acid sequence consisting of the amino acid residues at positions 21 to 128 is a variable region, and the amino acid sequence consisting of the amino acid residues at positions 129 to 233 is a constant region. In the hL02 light chain full-length nucleotide sequence shown in SEQ ID NO:62, the nucleotide sequence consisting of the nucleotides at positions 1 to 60 encodes the signal sequence, the nucleotide sequence consisting of the nucleotides at positions 61 to 384 encodes the variable region, and the nucleotide sequence consisting of the nucleotides at positions 385 to 699 encodes the constant region.

[0450] In the hL03 light chain full-length amino acid sequence shown in SEQ ID NO:65, the amino acid sequence consisting of the amino acid residues at positions 1 to 20 is a signal sequence, the amino acid sequence consisting of the amino acid residues at positions 21 to 128 is a variable region, and the amino acid sequence consisting of the amino acid residues at positions 129 to 233 is a constant region. In the hL03 light chain full-length nucleotide sequence shown in SEQ ID NO:66, the nucleotide sequence consisting of the nucleotides at positions 1 to 60 encodes the signal sequence, the nucleotide sequence consisting of the nucleotides at positions 61 to 384 encodes the variable region, and the nucleotide sequence consisting of the nucleotides at positions 385 to 699 encodes the constant region.

[0451] In the hL01 heavy chain full-length amino acid sequence shown in SEQ ID NO:69, the amino acid sequence consisting of the amino acid residues at positions 1 to 19 is a signal sequence, the amino acid sequence consisting of the amino acid residues at positions 20 to 141 is a variable region, and the amino acid sequence consisting of the amino acid residues at positions 142 to 471 is a constant region. In the hL01 heavy chain full-length nucleotide sequence shown in SEQ ID NO:70, the nucleotide sequence consisting of the nucleotides at positions 1 to 57 encodes the signal sequence, the nucleotide sequence consisting of the nucleotides at positions 58 to 423 encodes the variable region, and the nucleotide sequence consisting of the nucleotides at positions 424 to 1413 encodes the constant region.

[0452] In the hL02 heavy chain full-length amino acid sequence shown in SEQ ID NO:73, the amino acid sequence consisting of amino acid residues at positions 1 to 19 is a signal sequence, the amino acid sequence consisting of amino acid residues at positions 20 to 141 is a variable region, and the amino acid sequence consisting of amino acid residues at positions 142 to 471 is a constant region. In the hL02 heavy chain full-length nucleotide sequence shown in SEQ ID NO:74, the nucleotide sequence consisting of nucleotides at positions 1 to 57 encodes a signal sequence, the nucleotide sequence consisting of nucleotides at positions 58 to 423 encodes a variable region, and the nucleotide sequence consisting of nucleotides at positions 424 to 1413 encodes a constant region.

[0453] In the hL04 heavy chain full-length amino acid sequence shown in SEQ ID NO:77, the amino acid sequence consisting of the amino acid residues at positions 1 to 19 is a signal sequence, the amino acid sequence consisting of the amino acid residues at positions 20 to 141 is a variable region, and the amino acid sequence consisting of the amino acid residues at positions 142 to 471 is a constant region. In the hL04 heavy chain full-length nucleotide sequence shown in SEQ ID NO:78, the nucleotide sequence consisting of the nucleotides at positions 1 to 57 encodes the signal sequence, the nucleotide sequence consisting of the nucleotides at positions 58 to 423 encodes the variable region, and the nucleotide sequence consisting of the nucleotides at positions 424 to 1413 encodes the constant region.

[0454] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] In this specification, Tables 1-1 to 1-16 are also collectively referred to as Table 1.

[0455] Further examples of the antibodies of the present disclosure may include human antibodies that bind to CDH6.Anti-CDH6 human antibodies mean human antibodies that have only the gene sequence of antibodies derived from human chromosomes. Anti-CDH6 human antibodies can be obtained by a method using human antibody-producing mice having human chromosome fragments comprising heavy and light chain genes of human antibodies (see Tomizuka, K. et al., Nature Genetics (1997) 16, p. 133-143; Kuroiwa, Y. et al., Nucl. Acids Res. (1998) 26, p. 3447-3448; Yoshida, H. et al., Animal Cell Technology: Basic and Applied Aspects vol. 10, p. 69-73 (Kitagawa, Y., Matsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, p. 722-727; etc.).

[0456] Such human antibody-producing mice can be produced specifically by using genetically modified animals whose endogenous immunoglobulin heavy and light chain loci have been destroyed and instead have been subsequently introduced into human immunoglobulin heavy and light chain loci using yeast artificial chromosome (YAC) vectors or the like, then producing knockout animals and transgenic animals from such genetically modified animals, and then breeding such animals with each other.

[0457] Otherwise, anti-CDH6 human antibodies can also be obtained by: according to genetic recombination technology, using cDNA encoding each heavy chain and light chain of such human antibodies, or preferably transforming eukaryotic cells with a vector containing the cDNA and then culturing the transformed cells to produce genetically modified human monoclonal antibodies, so that the antibodies can be obtained from the culture supernatant.

[0458] In this context, for example, eukaryotic cells, and preferably mammalian cells, such as CHO cells, lymphocytes or myelomas, can be used as hosts.

[0459] In addition, methods for obtaining phage display-derived human antibodies that have been selected from human antibody libraries are also known (see Wormstone, IM et al., Investigative Ophthalmology & Visual Science. (2002) 43 (7), p. 2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), p. 189-203; Siriwardena, D. et al., Ophthalmology (2002) 109 (3), p. 427-431; etc.).

[0460] For example, a phage display method can be applied, which involves allowing the variable region of a human antibody to be expressed as a single chain antibody (scFv) on the surface of phage, and then selecting phage that binds to the antigen (Nature Biotechnology (2005), 23, (9), p.1105-1116).

[0461] By analyzing the genes of phage selected for their ability to bind to the antigen, the DNA sequence encoding the variable region of the human antibody that binds to the antigen can be determined.

[0462] Once the DNA sequence of the scFv that binds to the antigen is determined, an expression vector having the above sequence is produced, and the produced expression vector is then introduced into a suitable host and allowed to be expressed therein, thereby obtaining a human antibody (International Publication Nos. WO92 / 01047, WO92 / 20791, WO93 / 06213, WO93 / 11236, WO93 / 19172, WO95 / 01438 and WO95 / 15388, Annu. Rev. Immunol (1994) 12, p. 433-455, Nature Biotechnology (2005) 23 (9), p. 1105-1116).

[0463] If the newly generated human antibody binds to a partial peptide or partial three-dimensional structure to which any rat anti-human CDH6 antibody, chimeric anti-human CDH6 antibody or humanized anti-human CDH6 antibody described in the present specification (e.g., rG019 antibody, rG055 antibody, rG056 antibody, rG061 antibody, chG019 antibody, H01L02 antibody, H02L02 antibody, H02L03 antibody or H04L02 antibody) binds, it can be determined that the human antibody binds to the same epitope to which the rat anti-human CDH6 antibody, chimeric anti-human CDH6 antibody or humanized anti-human CDH6 antibody binds. On the other hand, by demonstrating that the human antibody competes with the rat anti-human CDH6 antibody, chimeric anti-human CDH6 antibody or humanized anti-human CDH6 antibody described in the present specification (e.g., rG019 antibody, rG055 antibody, rG056 antibody, rG061 antibody, chG019 antibody, H01L02 antibody, H02L02 antibody, H02L03 antibody or H04L02 antibody) in the binding of the antibody to CDH6 (e.g., the human antibody interferes with the rG019 antibody, The human antibody described in this specification can be determined to bind to the same epitope to which the rat anti-human CDH6 antibody, chimeric anti-human CDH6 antibody or humanized anti-human CDH6 antibody described in this specification binds, even if the specific sequence or structure of the epitope has not been determined. In the present specification, when it is determined that a human antibody "binds to the same epitope" by at least any one of these determination methods, it is concluded that the newly prepared human antibody "binds" to the "same epitope" as the rat anti-human CDH6 antibody, chimeric anti-human CDH6 antibody or humanized anti-human CDH6 antibody described in this specification. When the human antibody is confirmed to bind to the same epitope, it is expected that the human antibody should have equivalent biological activity as rat anti-human CDH6 antibody, chimeric anti-human CDH6 antibody, or humanized anti-human CDH6 antibody (e.g., rG019 antibody, rG055 antibody, rG056 antibody, rG061 antibody, chG019 antibody, H01L02 antibody, H02L02 antibody, H02L03 antibody, or H04L02 antibody).

[0464] The chimeric antibody, humanized antibody or human antibody obtained by the above method is evaluated for its binding activity to the antigen according to a known method or the like, thereby making it possible to select a preferred antibody.

[0465] An example of another index for comparing antibody properties may include the stability of the antibody. Differential scanning calorimeter (DSC) is a device that can quickly and accurately measure the midpoint of thermal denaturation (Tm), which serves as a good indicator of the relative structural stability of the protein. By using DSC to measure the Tm value and compare the obtained value, the difference in thermal stability can be compared. It is known that the storage stability of antibodies has a certain correlation with the thermal stability of antibodies (Lori Burton et al., Pharmaceutical Development and Technology (2007) 12, p.265-273), and therefore, thermal stability can be used as an index to select preferred antibodies. Other examples of indicators for selecting antibodies may include high yields in suitable host cells and low aggregation in aqueous solutions. For example, since the antibody with the highest yield does not always show the highest thermal stability, it is necessary to select the antibody most suitable for human administration by comprehensively determining it based on the above-mentioned index.

[0466] The antibodies of the present disclosure also include modifications of antibodies. The modifications are used to refer to antibodies of the present disclosure that are chemically or biologically modified. Examples of such chemical modifications include the combination of chemical moieties with amino acid backbones, and chemical modifications of N-linked or O-linked carbohydrate chains. Examples of such biological modifications include antibodies that have undergone post-translational modifications (e.g., N-linked or O-linked glycosylation, N-terminal or C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, and conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamic acid), and antibodies to which methionine residues have been added to their N-termini as a result of expression using prokaryotic host cells. In addition, such modifications also mean antibodies that include labels that enable detection or separation of antibodies or antigens of the present disclosure, such as enzymatically labeled antibodies, fluorescently labeled antibodies, and affinity-labeled antibodies. Such modifications of antibodies of the present disclosure can be used to improve the stability and retention of antibodies in blood; reduce antigenicity; detect or separate antibodies or antigens; etc.

[0467] In addition, by regulating the sugar chain modification (glycosylation, de-fucosylation, etc.) bound to the antibody of the present disclosure, the antibody-dependent cellular toxicity activity can be enhanced. As a technique for regulating the sugar chain modification of an antibody, those described in International Publication Nos. WO1999 / 54342, WO2000 / 61739, and WO2002 / 31140, etc. are known, although the technique is not limited thereto. The antibody of the present disclosure also includes an antibody in which the above-mentioned sugar chain modification has been regulated.

[0468] Once the antibody gene is isolated, the gene can be introduced into a suitable host using an appropriate combination of a host and an expression vector to produce the antibody. A specific example of an antibody gene can be a combination of a gene encoding the heavy chain sequence of the antibody described in this specification and a gene encoding the light chain sequence of the antibody described therein. When transforming a host cell, such heavy chain sequence genes and light chain sequence genes can be inserted into a single expression vector, or conversely, these genes can be each inserted into a different expression vector.

[0469] When eukaryotic cells are used as hosts, animal cells, plant cells or eukaryotic microorganisms can be used. Specifically, examples of animal cells may include mammalian cells, such as COS cells (Gluzman, Y., Cell (1981) 23, p. 175-182, ATCC CRL-1650), mouse fibroblasts NIH3T3 (ATCC No. CRL-1658), dihydrofolate reductase-deficient cell lines of Chinese hamster ovary cells (CHO cells, ATCC CCL-61) (Urlaub, G. and Chasin, LA Proc. Natl. Acad. Sci. USA (1980) 77, p. 4126-4220) and FreeStyle 293F cells (Invitrogen Corp.).

[0470] When a prokaryotic cell is used as a host, for example, Escherichia coli or Bacillus subtilis can be used.

[0471] The antibody gene of interest is introduced into these cells for transformation, and the transformed cells are then cultured in vitro to obtain the antibody. In the above-mentioned culture, there are cases where the yield varies depending on the sequence of the antibody, and therefore it is possible to use the yield as an indicator to select antibodies produced as drugs from antibodies with equivalent binding activity. Therefore, the antibodies of the present disclosure also include antibodies obtained by the above-mentioned method for producing antibodies, which includes the steps of culturing the transformed host cells and collecting the antibody of interest or the functional fragment of the antibody from the culture obtained in the above-mentioned steps.

[0472] It is known that the lysine residue at the carboxyl terminus of the heavy chain of antibodies produced in cultured mammalian cells is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and similarly, it is known that two amino acid residues, glycine and lysine, at the carboxyl terminus of the heavy chain are deleted, and the proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletions and modifications of these heavy chain sequences have no effect on the antigen-binding activity and effector function (activation of complement, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, the antibodies according to the present disclosure also include antibodies that have undergone the above modifications, and functional fragments of the antibodies, and specific examples of such antibodies include deletion mutants comprising a deletion of 1 or 2 amino acids at the carboxyl terminus of the heavy chain, and deletion mutants formed by amidating the above deletion mutants (e.g., a heavy chain in which the proline residue at the carboxyl terminal site is amidated). However, deletion mutants involving the carboxyl terminus deletion of the heavy chain of the antibody according to the present disclosure are not limited to the above-mentioned deletion mutants, as long as they retain antigen binding activity and effector function. The two heavy chains constituting the antibody according to the present disclosure can be any type of heavy chain selected from the full-length antibody and the above-mentioned deletion mutants, or can be a combination of any two types selected from the above-mentioned groups. The ratio of each deletion mutant can be affected by the type and culture conditions of the cultured mammalian cells producing the antibody according to the present disclosure. Examples of the main components of the antibody according to the present disclosure may include antibodies in which one amino acid residue is deleted at each carboxyl terminus of the two heavy chains.

[0473] Examples of the antibody isotype of the present disclosure may include IgG (IgG1, IgG2, IgG3, and IgG4). Among them, IgG1 and IgG4 are preferred.

[0474] Examples of the biological activity of antibodies may generally include antigen binding activity, activity of being internalized into cells expressing the antigen by binding to the antigen, activity of neutralizing antigen activity, activity of enhancing antigen activity, antibody-dependent cellular cytotoxicity (ADCC) activity, complement-dependent cytotoxicity (CDC) activity, and antibody-dependent cellular phagocytosis (ADCP). The function of the antibody according to the present disclosure is binding activity against CDH6, and preferably activity of being internalized into cells expressing CDH6 by binding to CDH6. In addition, the antibody of the present disclosure may have ADCC activity, CDC activity, and / or ADCP activity, as well as cell internalization activity.

[0475] The antibody obtained can be purified to a homogeneous state. For the separation and purification of antibodies, separation and purification methods for common proteins can be used. For example, column chromatography, filtration, ultrafiltration, salting out, dialysis, preparative polyacrylamide gel electrophoresis and isoelectric focusing are appropriately selected and combined with each other so that antibodies can be separated and purified (Strategies for Protein Purification and Characterization: A Laboratory Course Manual, Daniel R. Marshak et al., Cold Spring Harbor Laboratory Press (1996); and Antibodies: A Laboratory Manual. Ed Harlow and David Lane, Cold Spring Harbor Laboratory (1988)), although the example of separation and purification methods is not limited thereto.

[0476] Examples of chromatography may include affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration chromatography, reverse phase chromatography, and absorption chromatography.

[0477] These chromatographic techniques can be performed using liquid chromatography such as HPLC or FPLC.

[0478] Examples of the column used in affinity chromatography may include a protein A column and a protein G column. Examples of the column using protein A may include Hyper D, POROS, and Sepharose FF (Pharmacia).

[0479] Likewise, using an antigen-immobilized carrier, antibodies can be purified by utilizing the binding activity of antibodies to antigens.

[0480] 3. Anti-CDH6 Antibody-Drug Conjugates (1) Drugs The anti-CDH6 antibody obtained in the above-mentioned "2. Production of anti-CDH6 antibodies" can be conjugated to a drug via a linker structure portion to prepare an anti-CDH6 antibody-drug conjugate. The drug is not particularly limited as long as it has a substituent or a partial structure that can be connected to the linker structure. Depending on the conjugated drug, the anti-CDH6 antibody-drug conjugate can be used for various purposes. Examples of such drugs can include substances having anti-tumor activity, substances effective for blood diseases, substances effective for autoimmune diseases, anti-inflammatory substances, antimicrobial substances, antifungal substances, antiparasitic substances, antiviral substances, and anti-anesthetic substances.

[0481] (1)-1<Antitumor Compounds> The following describes an example of using an anti-tumor compound as a compound conjugated in the anti-CDH6 antibody-drug conjugate of the present disclosure. The anti-tumor compound is not particularly limited as long as the compound has an anti-tumor effect and has a substituent or a partial structure that can be connected to the linker structure. When part or all of the linker is cut in tumor cells, the anti-tumor compound portion is released, so that the anti-tumor compound exhibits an anti-tumor effect. When the linker is cleaved at the connection position with the drug, the anti-tumor compound is released with its original structure to exert its original anti-tumor effect.

[0482] The anti-CDH6 antibody obtained in the above-mentioned "2. Production of anti-CDH6 antibody" can be conjugated with an anti-tumor compound via a linker structure moiety to prepare an anti-CDH6 antibody-drug conjugate.

[0483] As an example of an antitumor compound used in the present disclosure, the camptothecin derivative exotecan (represented by the following formula: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione) can be preferably used.

[0484] [Formula 13] The compound can be obtained by, for example, the method described in U.S. Patent Publication No. US2016 / 0297890 or other known methods, and the amino group at position 1 may be preferably used as the connection position to the linker structure. Further, when a part of the linker is still attached thereto, exitecan may be released in tumor cells. However, even in this state, the compound exerts an excellent antitumor effect.

[0485] Since exotecan has a camptothecin structure, it is known that in an acidic aqueous medium (e.g., about pH 3), the equilibrium shifts toward a structure having a formed lactone ring (closed ring), whereas in an alkaline aqueous medium (e.g., about pH 10), the equilibrium shifts toward a structure having an opened lactone ring (open ring). Drug conjugates into which exotecan residues corresponding to such closed ring structures and open ring structures have been introduced are also expected to have equivalent antitumor effects, and needless to say, any such drug conjugates are included in the scope of the present disclosure.

[0486] Other examples of antitumor compounds may include antitumor compounds described in the literature (Pharmacological Reviews, 68, p. 3-19, 2016). Specific examples thereof may include doxorubicin, calicheamicin, dolastatin 10, auristatins such as monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF), maytansinoids such as DM1 and DM4, pyrrolobenzodiazepines, Dimer SG2000 (SJG-136), camptothecin derivative SN-38, duocarcins such as CC-1065, amatoxin, daunorubicin, mitomycin C, bleomycin, cyclocytidine, vincristine, vinblastine, methotrexate, platinum-based antitumor agents (cisplatin and its derivatives), and paclitaxel and its derivatives.

[0487] In antibody-drug conjugates, the number of drug molecules conjugated to each antibody molecule is a key factor that has an impact on its efficacy and safety. The production of antibody-drug conjugates is achieved by specifying the reaction conditions such as the amount of raw materials and reagents used for the reaction, so as to obtain a constant number of conjugated drug molecules. Unlike the chemical reaction of low molecular weight compounds, a mixture containing different numbers of conjugated drug molecules is usually obtained. The number of drug molecules conjugated to each antibody molecule is defined and expressed as an average value, that is, the average number of conjugated drug molecules. Unless otherwise specified, that is, except for the case of an antibody-drug conjugate with a specific number of conjugated drug molecules included in an antibody-drug conjugate mixture with different numbers of conjugated drug molecules, the number of conjugated drug molecules according to the present disclosure is also generally meant to be an average value. The number of exotecan molecules conjugated to the antibody molecule is controllable, and as the average number of drug molecules conjugated to each antibody, about 1 to 10 exotecan molecules can be conjugated. The number of isotecan molecules is preferably 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8 or 7 to 8, more preferably 5 to 8, further preferably 7 to 8, and further preferably 8. It should be noted that those skilled in the art can design a reaction for conjugating a desired number of drug molecules to antibody molecules based on the description in the examples of the present application, and can obtain an antibody-drug conjugate with a controllable number of conjugated isotecan molecules.

[0488] (2) Joint structure The linker structure for conjugating a drug to the anti-CDH6 antibody in the anti-CDH6 antibody-drug conjugate of the present disclosure will be described.

[0489] In the antibody-drug conjugate of the present application, the anti-CDH6 antibody is conjugated to the linker structure of the drug without particular limitation, as long as the resulting antibody-drug conjugate can be used. The linker structure can be appropriately selected and used according to the purpose of use. An example of a linker structure can include a linker described in a known document (Pharmacol Rev 68: 3-19, January 2016, Protein Cell DOI 10.1007 / s13238-016-0323-0, etc.). Further specific examples thereof may include VC (valine-citrulline), MC (maleimidocaproyl), SMCC (succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate), SPP (N-succinimidyl 4-(2-pyridyldithio)pentanoate, SS (disulfide), SPDB (N-succinimidyl 4-(2-pyridyldithio)butanoate, SS / hydrazone, hydrazone and carbonate.

[0490] Another example may include the joint structure described in U.S. Patent Publication No. US2016 / 0297890 (as an example, those described in its paragraphs

[0260] to

[0289] ). Any joint structure given below may preferably be used. It should be noted that the left end of the structure is the connection position with the antibody, and the right end is the connection position with the drug. In addition, GGFG (SEQ ID NO: 89) in the joint structure given below represents an amino acid sequence consisting of glycine-glycine-phenylalanine-glycine (GGFG) (SEQ ID NO: 89) connected by a peptide bond.

[0491] -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)- and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-.

[0492] More preferred are the following: -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)- and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-.

[0493] Still more preferred are the following: -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)- and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-.

[0494] The antibody is linked to the terminal of -(succinimidyl-3-yl-N) (for example, the terminal opposite to the terminal to which -CH2CH2CH2CH2CH2- is linked in "-(succinimidyl-3-yl-N)-CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-" (the left terminal)), and the antitumor compound is linked to the terminal opposite to the terminal to which the antibody is linked to -(succinimidyl-3-yl-N) (the carbonyl group of CH2-O-CH2-C(=O)- at the right terminal in the above example). "-(succinimidyl-3-yl-N)-" has a structure shown in the following formula: [Formula 14] Position 3 of the partial structure is the connection position with the anti-CDH6 antibody. The connection with the antibody at position 3 is characterized by forming a thioether bond. The nitrogen atom at position 1 of the partial structure is connected to the carbon atom of the methylene group present in the linker of the structure.

[0495] In the antibody-drug conjugate of the present disclosure with exotecan as a drug, a drug linker moiety having any of the structures given below is preferably used for conjugation with the antibody. For these drug-linker moieties, the average number of conjugations per antibody may be 1 to 10, and preferably 2 to 8, more preferably 5 to 8, further preferably 7 to 8, and even more preferably 8.

[0496] -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX), -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX), -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX), -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX) and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX).

[0497] More preferred are the following: -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX), -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX) and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX).

[0498] Still more preferred are the following: -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX).

[0499] -(NH-DX) has the structure shown below: [Formula 15] And it represents a group derived by removing one hydrogen atom from the amino group at position 1 of exitecan.

[0500] (3) Method for producing antibody-drug conjugates The antibody that can be used in the antibody-drug conjugate of the present disclosure is not particularly limited as long as it is an anti-CDH6 antibody having internalization activity or a functional fragment of the antibody, as described in the above section “2. Production of anti-CDH6 antibodies” and in the Examples.

[0501] Next, a typical method for producing the antibody-drug conjugate of the present disclosure will be described. It should be noted that in the following description, the "Compound No." shown in each reaction scheme is used to represent the compound. Specifically, each compound is referred to as "the compound of formula (1)", "Compound (1)", etc. The same is true for other compound Nos.

[0502] (3)-1 Preparation method 1 The antibody-drug conjugate represented by the formula (1) given below, in which the anti-CDH6 antibody is linked to the linker structure via a thioether, can be produced by reacting an antibody having a thiol group converted from a disulfide bond by reduction of the anti-CDH6 antibody with a compound (2), which can be obtained by a known method (for example, it can be obtained by the method described in patent publication US2016 / 297890 (for example, the method described in paragraphs

[0336] to

[0374] )). The antibody-drug conjugate can be produced, for example, by the following method.

[0503] [Expression 1] AB represents an antibody with a sulfhydryl group, and L 1 has a structure represented by -(succinimidyl-3-yl-N)-, and L1 ' represents a maleimide group represented by the following formula.

[0504] [Formula 16] -L 1 -L X Having a structure represented by any of the following formulas: -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)- and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-.

[0505] Among them, the following are more preferred: -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-, -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)- and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-.

[0506] Further preferred are the following: -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)- and -(Succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-.

[0507] In the above reaction scheme, the antibody-drug conjugate (1) can be understood to have a structure in which one structural part from the drug to the end of the linker is linked to one antibody. However, the description is given for the sake of convenience, and in fact there are many cases in which a plurality of the above structural parts are linked to one antibody molecule. The same applies to the explanation of the production method described below.

[0508] Specifically, the antibody-drug conjugate (1) can be produced by reacting a compound (2) obtainable by a known method (for example, obtainable by the method described in patent publication US2016 / 297890 (for example, obtainable by the method described in paragraphs

[0336] to

[0374] )) with an antibody (3a) having a thiol group.

[0509] Antibodies (3a) having thiol groups can be obtained by methods well known to those skilled in the art (Hermanson, GT, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press (1996)). Examples of methods may include, but are not limited to: Traut's reagent reacting with amino groups of antibodies; S-acetylthioalkanoic acid N-succinimidyl ester reacting with amino groups of antibodies, followed by reaction with hydroxylamine; 3-(pyridyldithio)propionic acid N-succinimidyl ester reacting with antibodies, followed by reaction with reducing agents; antibodies reacting with reducing agents such as dithiothreitol, 2-mercaptoethanol or tris(2-carboxyethyl)phosphine hydrochloride (TCEP) to reduce interchain disulfide bonds in antibodies to form thiol groups.

[0510] Specifically, by using 0.3-3 molar equivalents of TCEP as a reducing agent for each interchain disulfide bond in the antibody, and reacting the reducing agent with the antibody in a buffer solution containing a chelating agent, an antibody with partially or completely reduced interchain disulfide bonds can be obtained. Examples of chelating agents can include ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). The chelating agent can be used at a concentration of 1mM to 20mM. Solutions of sodium phosphate, sodium borate, sodium acetate, etc. can be used as buffer solutions. As a specific example, by reacting the antibody with TCEP at 4°C-37°C for 1-4 hours, an antibody (3a) with partially or completely reduced sulfhydryl groups can be obtained.

[0511] Notably, the drug-linker moiety can be conjugated via a thiol bond by performing an addition reaction of a thiol group to the drug-linker moiety.

[0512] Then, using 2 to 20 molar equivalents of compound (2) per antibody (3a) having a sulfhydryl group, an antibody-drug conjugate (1) in which 2 to 8 drug molecules are conjugated per antibody can be produced. Specifically, a solution containing the compound (2) dissolved therein can be added to a buffer solution containing the antibody (3a) having a sulfhydryl group for reaction. In the context, sodium acetate solution, sodium phosphate, sodium borate, etc. can be used as a buffer solution. The pH of the reaction is 5 to 9, and more preferably, the reaction can be carried out at close to pH 7. Organic solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA) or N-methyl-2-pyrrolidone (NMP) can be used as solvents for dissolving compound (2). The reaction can be carried out by adding a solution containing a compound (2) dissolved in an organic solvent at 1 to 20% v / v to a buffer solution containing an antibody (3a) having a sulfhydryl group. The reaction temperature is 0-37°C, more preferably 10-25°C, and the reaction time is 0.5-2 hours. The reaction can be terminated by inactivating the reactivity of the unreacted compound (2) with a thiol-containing reagent. The thiol-containing reagent is, for example, cysteine ​​or N-acetyl-L-cysteine ​​(NAC). More specifically, the reaction can be terminated by adding 1 to 2 molar equivalents of NAC to the compound (2) used and incubating the obtained mixture at room temperature for 10 to 30 minutes.

[0513] (4) Identification of Antibody-Drug Conjugates The produced antibody-drug conjugate (1) can be subjected to concentration, buffer exchange, purification, and measurement of antibody concentration and the average number of drug molecules conjugated per antibody molecule according to the following general procedures to identify the antibody-drug conjugate (1).

[0514] (4)-1 General Procedure A: Concentration of an Aqueous Solution of an Antibody or Antibody-Drug Conjugate The solution of the antibody or antibody-drug conjugate is added to an Amicon Ultra (50,000 MWCO, Millipore Corporation) container, and the solution of the antibody or antibody-drug conjugate is concentrated by centrifugation (at 2000 G to 3800 G for 5 to 20 minutes) using a centrifuge (Allegra X-15R, Beckman Coulter, Inc.).

[0515] (4)-2 General Procedure B: Measurement of Antibody Concentration The antibody concentration was measured using a UV detector (Nanodrop 1000, Thermo Fisher Scientific Inc.) according to the manufacturer's method. In this regard, different absorption coefficients at 280 nm between antibodies (1.3 mL mg -1 cm -1 Up to 1.8 mL mg -1 cm -1 ).

[0516] (4)-3 General Procedure C: Antibody Buffer Replacement According to the method defined by the manufacturer, a NAP-25 column (Cat. No. 17-0852-02, GE Healthcare Japan Corporation) using a Sephadex G-25 carrier was balanced with a phosphate buffer (50 mM, pH 6.0) containing sodium chloride (50 mM) and EDTA (2 mM) (referred to as PBS6.0 / EDTA in this specification). An aqueous solution of the antibody was applied in an amount of 2.5 mL per NAP-25 column, and thereafter the fractions (3.5 mL) eluted with 3.5 mL of PBS6.0 / EDTA were collected. The fractions were concentrated by General Procedure A. After measuring the antibody concentration using General Procedure B, the antibody concentrate was adjusted to 20 mg / mL using PBS6.0 / EDTA.

[0517] (4)-4 General Procedure D: Purification of Antibody-Drug Conjugates The NAP-25 column is equilibrated with any commercially available buffer solution, such as acetate buffer (10 mM, pH 5.5; referred to as ABS in this specification) containing sorbitol (5%). The aqueous reaction solution (about 2.5 mL) of the antibody-drug conjugate is applied to the NAP-25 column, and thereafter eluted with an amount of buffer solution defined by the manufacturer to collect the antibody fraction. The gel filtration purification process in which the collected fraction is applied to the NAP-25 column again and eluted with the buffer solution is repeated a total of 2-3 times to obtain an antibody-drug conjugate excluding non-conjugated drug linkers and low molecular weight compounds (tris(2-carboxyethyl)phosphine hydrochloride (TCEP), N-acetyl-L-cysteine ​​(NAC) and dimethyl sulfoxide).

[0518] (4)-5 General Procedure E: Measurement of Antibody Concentration in Antibody-Drug Conjugates and the Average Number of Drug Molecules Conjugated per Antibody Molecule The conjugated drug concentration in the antibody-drug conjugate can be calculated by measuring the UV absorbance of the antibody-drug conjugate aqueous solution at two wavelengths, 280 nm and 370 nm, and thereafter performing the calculation as shown below.

[0519] The total absorbance at any given wavelength is equal to the sum of the absorbances of all light absorbing chemical species present in the system [additivity of absorbance]. Therefore, based on the assumption that the molar absorption coefficients of the antibody and drug are unchanged between before and after antibody and drug conjugation, the antibody concentration and drug concentration in the antibody-drug conjugate can be expressed by the following equations.

[0520] A 280 =A D,280 +A A,280 =ε D,280 C D +ε A,280 C A Equation (1) A 370 =A D,370 +A A,370 =ε D,370 C D +ε A,370 C A Equation (2) In the context described, A 280 represents the absorbance of the aqueous solution of antibody-drug conjugate at 280 nm, A 370 represents the absorbance of the aqueous solution of antibody-drug conjugate at 370 nm, A A,280 represents the absorbance of the antibody at 280 nm, A A,370 represents the absorbance of the antibody at 370 nm, A D,280represents the absorbance of the conjugate precursor at 280 nm, A D,370 represents the absorbance of the conjugate precursor at 370 nm, ε A,280 represents the molar absorption coefficient of the antibody at 280 nm, ε A,370 represents the molar absorption coefficient of the antibody at 370 nm, ε D,280 represents the molar absorption coefficient of the conjugate precursor at 280 nm, ε D,370 represents the molar absorption coefficient of the conjugate precursor at 370 nm, C A represents the antibody concentration in the antibody-drug conjugate, and C D represents the drug concentration in the antibody-drug conjugate.

[0521] In the context described, regarding ε A,280 , ε A,370 , ε D,280 and ε D,370 , using a preliminarily prepared value (an estimated value based on a calculated or measured value obtained by UV measurement of the compound). For example, ε can be estimated from the amino acid sequence of the antibody by a known calculation method (Protein Science, 1995, vol. 4, 2411-2423) A,280 ε A,370 Usually zero. D,280 and ε D,370 It can be obtained by measuring the absorbance of a solution in which the conjugate precursor used is dissolved at a certain molar concentration according to the Lambert-Beer law (absorbance = molar concentration × molar absorption coefficient × optical path length of the measuring cell). 280 and A 370 , and then by substituting these values ​​and solving the simultaneous equations (1) and (2), C A and C D Furthermore, by D Divide by C A , the average number of drug molecules conjugated per antibody can be determined.

[0522] (4)-6 General Procedure F: Measurement of the average number of drug molecules conjugated per antibody molecule in an antibody-drug conjugate-(2) In addition to the aforementioned "(4)-5 General Procedure E", the average number of drug molecules conjugated per antibody molecule in the antibody-drug conjugate can also be determined by high performance liquid chromatography (HPLC) analysis using the following method. Hereinafter, a method for measuring the average number of conjugated drug molecules by HPLC when the antibody and the drug linker are conjugated via a disulfide bond will be described. Those skilled in the art will be able to refer to the method and appropriately measure the average number of conjugated drug molecules by HPLC depending on the connection mode between the antibody and the drug linker.

[0523] F-1. Preparation of samples for HPLC analysis (reduction of antibody-drug conjugate) The antibody-drug conjugate solution (about 1 mg / mL, 60 μL) was mixed with an aqueous solution of dithiothreitol (DTT) (100 mM, 15 μL). The disulfide bond between the light chain and the heavy chain of the antibody-drug conjugate was cleaved by incubating the mixture at 37°C for 30 minutes. The resulting sample was used for HPLC analysis.

[0524] F-2.HPLC analysis HPLC analysis was performed under the following measurement conditions.

[0525] HPLC system: Agilent 1290 HPLC system (Agilent Technologies, Inc.) Detector: UV absorption spectrometer (measurement wavelength: 280nm) Column: ACQUITY UPLC BEH Phenyl (2.1×50 mm, 1.7 μm, 130 angstroms; Waters Corp., P / N 186002884) Column temperature: 80°C Mobile phase A: 0.10% trifluoroacetic acid (TFA) and 15% 2-propanol in water Mobile phase B: 0.075% TFA and 15% 2-propanol in acetonitrile Gradient program: 14%-36% (0 min-15 min), 36%-80% (15 min-17 min), 80%-14% (17 min-17.01 min) and 14% (17.01 min-25 min) Sample injection: 10 μL F-3. Data Analysis F-3-1. Compared with the unconjugated antibody light chain (L0) and heavy chain (H0), the light chain bound to one or more drug molecules (the light chain bound to i drug molecules: L i ) and a heavy chain that binds to one or more drug molecules (heavy chain that binds to i drug molecules: H i) show a higher hydrophobicity proportional to the number of conjugated drug molecules and therefore have a longer retention time. Therefore, these chains are eluted in the following order, for example, L0 and L1 or H0, H1, H2 and H3. By comparing the retention times of L0 and H0, the detection peak can be assigned to any one of L0, L1, H0, H1, H2 or H3. The number of conjugated drug molecules can be defined by those skilled in the art, but preferably L0, L1, H0, H1, H2 and H3.

[0526] F-3-2. Since the drug linker has UV absorption, the peak area value was corrected according to the number of conjugated drug linker molecules using the molar absorption coefficients of the light chain or heavy chain and the drug linker according to the following expression.

[0527] [Expression 2] [Expression 3] In the context, the value estimated from the amino acid sequence of the light chain or heavy chain of each antibody by a known calculation method (Protein Science, 1995, vol. 4, 2411-2423) can be used as the molar absorption coefficient (280 nm) of the light chain or heavy chain of the antibody. In the case of H01L02, a molar absorption coefficient of 31710 and a molar absorption coefficient of 79990 were used as estimated values ​​for the light chain and the heavy chain, respectively, according to the amino acid sequence of the antibody. The molar absorption coefficient (280 nm) of the actual measurement of the compound, in which the maleimide group has been converted into succinimide thioether by the reaction of each drug linker with mercaptoethanol or N-acetylcysteine, is used as the molar absorption coefficient (280 nm) of the drug linker. The wavelength for absorbance measurement can be appropriately set by those skilled in the art, but is preferably a wavelength at which the antibody peak can be measured, and more preferably 280 nm.

[0528] F-3-3. The peak area ratio (%) of each chain was calculated in consideration of the total number of peak area correction values ​​according to the following expression.

[0529] [Expression 4] F-3-4. The average number of drug molecules conjugated per antibody molecule in the antibody-drug conjugate was calculated according to the following expression.

[0530] Average number of conjugated drug molecules = (L0 peak area ratio x 0 + L1 peak area ratio x 1 + H0 peak area ratio x 0 + H1 peak area ratio x 1 + H2 peak area ratio x 2 + H3 peak area ratio x 3) / 100 x 2 It should be noted that in order to ensure the amount of antibody-drug conjugates, multiple antibody-drug conjugates having almost the same average number of conjugated drug molecules (e.g., about ± 1) that have been produced under similar conditions can be mixed to prepare a new batch. In such a case, the average number of drug molecules in the new batch falls between the average number of drug molecules before mixing.

[0531] One specific example of an antibody-drug conjugate of the present disclosure may include a drug having the formula: [Formula 17] Or the following: [Formula 18] Representation of the structure of the antibody-drug conjugate.

[0532] In the context, AB represents the anti-CDH6 antibody disclosed in this specification, and the antibody is conjugated to the drug linker via a sulfhydryl group originating from the antibody. In the context, n has the same meaning as the so-called DAR (drug to antibody ratio), and represents the drug to antibody ratio of each antibody. Specifically, n represents the number of drug molecules conjugated to each antibody molecule, which is a numerical value defined and expressed as an average value, that is, the average number of conjugated drug molecules. In the case of an antibody-drug conjugate represented by [Formula 17] or [Formula 18] of the present disclosure, in the measurement by ordinary procedure F, n can be 2 to 8, and preferably 5 to 8, more preferably 7 to 8, and still more preferably 8.

[0533] One example of the antibody-drug conjugate of the present disclosure may include an antibody-drug conjugate having a structure represented by the above-mentioned formula [Formula 17] or [Formula 18], wherein the antibody represented by AB includes any one selected from the following antibodies (a) to (g), or a functional fragment of the antibody, or a pharmacologically acceptable salt of the antibody-drug conjugate: (a) an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length light chain amino acid sequence shown in SEQ ID NO:61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length heavy chain amino acid sequence shown in SEQ ID NO:69; (b) an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length light chain amino acid sequence shown in SEQ ID NO:61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length heavy chain amino acid sequence shown in SEQ ID NO:73; (c) an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length light chain amino acid sequence shown in SEQ ID NO:61, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length heavy chain amino acid sequence shown in SEQ ID NO:77; (d) an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length light chain amino acid sequence shown in SEQ ID NO:65, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length heavy chain amino acid sequence shown in SEQ ID NO:69; (e) an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length light chain amino acid sequence shown in SEQ ID NO:65, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length heavy chain amino acid sequence shown in SEQ ID NO:73; (f) an antibody consisting of a light chain and a heavy chain, the light chain consisting of the amino acid sequence at positions 21 to 233 in the full-length light chain amino acid sequence shown in SEQ ID NO:65, and the heavy chain consisting of the amino acid sequence at positions 20 to 471 in the full-length heavy chain amino acid sequence shown in SEQ ID NO:77; and (g) any one of antibodies (a) to (f), wherein the heavy chain or light chain comprises one or two or more modifications selected from post-translational modifications, wherein the post-translational modifications are represented by N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of methionine residues to the N-terminus, amidation of proline residues, and conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids at the carboxyl terminus.

[0534] 4. Medication Since the anti-CDH6 antibody of the present disclosure or a functional fragment of the antibody described in the previous section “2. Production of anti-CDH6 antibodies” and the examples binds to CDH6 on the surface of tumor cells and has internalization activity, it can be used as a drug alone or in combination with additional drugs, and in particular as a therapeutic agent for cancer, such as renal cell tumors or ovarian tumors, such as renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, bile duct cancer, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor or neuroblastoma.

[0535] Furthermore, the anti-CDH6 antibodies of the present disclosure or functional fragments of the antibodies can be used to detect cells expressing CDH6.

[0536] Furthermore, since the anti-CDH6 antibody of the present disclosure or a functional fragment of the antibody has internalization activity, it can be used as an antibody in an antibody-drug conjugate.

[0537] When a drug having anti-tumor activity such as cytotoxic activity is used as a drug, the anti-CDH6 antibody-drug conjugate of the present disclosure described in the above section "3. Anti-CDH6 antibody-drug conjugate" and the Examples is a conjugate of an anti-CDH6 antibody having internalization activity and / or a functional fragment of the antibody and a drug having anti-tumor activity such as cytotoxic activity. Because the anti-CDH6 antibody-drug conjugate exhibits anti-tumor activity against cancer cells expressing CDH6, it can be used as a drug, and in particular, as a therapeutic and / or preventive agent for cancer.

[0538] The anti-CDH6 antibody-drug conjugates of the present disclosure may absorb moisture or have adsorbed water, for example, to become hydrated when left in the air or undergoing recrystallization or purification procedures. Such water-containing compounds or pharmacologically acceptable salts are also included in the present disclosure.

[0539] When the anti-CDH6 antibody-drug conjugate of the present disclosure has a basic group such as an amino group, it can form a pharmacologically acceptable acid addition salt if desired. Examples of such acid addition salts may include: hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides and hydroiodides; inorganic acid salts such as nitrates, perchlorates, sulfates and phosphates; lower alkanesulfonates such as methanesulfonates, trifluoromethanesulfonates and ethanesulfonates; arylsulfonates such as benzenesulfonates and p-toluenesulfonates; organic acid salts such as formates, acetates, trifluoroacetates, malates, fumarates, succinates, citrates, tartrates, oxalates and maleates; and amino acid salts such as ornithines, glutamates and aspartates.

[0540] When the anti-CDH6 antibody-drug conjugate of the present disclosure has an acidic group such as a carboxyl group, it can form a pharmacologically acceptable base addition salt if desired. Examples of such base addition salts may include: alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as dibenzylamine salts, morpholine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, diethylamine salts, triethylamine salts, cyclohexylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, diethanolamine salts, N-benzyl-N-(2-phenylethoxy)amine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminomethane salts.

[0541] The present disclosure may also include anti-CDH6 antibody-drug conjugates, wherein one or more atoms constituting the antibody-drug conjugate are replaced with isotopes of the atoms. There are two types of isotopes: radioisotopes and stable isotopes. Examples of isotopes may include isotopes of hydrogen (2H and 3H), isotopes of carbon (11C, 13C and 14C), isotopes of nitrogen (13N and 15N), isotopes of oxygen (15O, 17O and 18O) and isotopes of fluorine (18F). Compositions containing antibody-drug conjugates labeled with such isotopes are useful as, for example, therapeutic agents, preventive agents, research reagents, assay reagents, diagnostic agents, and in vivo diagnostic imaging agents. Each isotopically labeled antibody-drug conjugate, as well as mixtures of isotopically labeled antibody-drug conjugates at any given ratio are included in the present disclosure. The antibody-drug conjugate labeled with an isotope can be prepared, for example, according to methods known in the art by using a raw material labeled with an isotope instead of a raw material used in the production method of the present disclosure mentioned later.

[0542] For example, in vitro cytotoxicity can be measured based on the activity of inhibiting cell proliferation reaction. For example, a cancer cell line overexpressing CDH6 is cultured, and an anti-CDH6 antibody-drug conjugate is added to the culture system at different concentrations. Thereafter, its inhibitory activity for lesion formation, colony formation and spheroid growth can be measured. In the context, for example, by using a renal cell tumor- or ovarian tumor-derived cancer cell line, the cell growth inhibitory activity for renal cell tumors or ovarian tumors can be examined.

[0543] The in vivo therapeutic effect on cancer in experimental animals can be measured, for example, by administering an anti-CDH6 antibody-drug conjugate to nude mice that have been inoculated with a tumor cell line that highly expresses CDH6, and then measuring changes in cancer cells. In this context, for example, by using an animal model derived from immunodeficient mice by inoculation of renal cell carcinoma-, renal clear cell carcinoma-, papillary renal cell carcinoma-, ovarian cancer-, ovarian serous adenocarcinoma-, or thyroid cancer-derived cells, the therapeutic effect on renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, or thyroid cancer can be measured.

[0544] The type of cancer to which the anti-CDH6 antibody-drug conjugate of the present disclosure is applied is not particularly limited, as long as the cancer expresses CDH6 in the cancer cells to be treated. Examples thereof may include renal cell carcinoma (e.g., renal clear cell carcinoma or papillary renal cell carcinoma), ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, bile duct cancer, lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor and neuroblastoma, although the cancer is not limited thereto, as long as the cancer expresses CDH6. Examples thereof may also include renal cell carcinoma, clear cell renal carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, clear cell carcinoma of the ovary, endometrioid carcinoma of the ovary, ovarian mucinous tumors, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumors, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, nasopharyngeal carcinoma, prostate cancer, or cancer associated with von Schiele-Lin disease. Preferred examples thereof can include renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, ovarian clear cell carcinoma, ovarian endometrioid carcinoma, ovarian mucinous tumor, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor and neuroblastoma. Preferred examples of cancer can include renal cell carcinoma (e.g., renal clear cell carcinoma or papillary renal cell carcinoma) and ovarian cancer. Preferred examples of cancer include ovarian cancer (e.g., epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer). Cancer can be metastatic.

[0545] The anti-CDH6 antibody-drug conjugates of the present disclosure can be preferably administered to mammals, and more preferably administered to humans.

[0546] Pharmaceutical composition and mode of administration Substances used in the pharmaceutical composition including the anti-CDH6 antibody-drug conjugate of the present disclosure may be appropriately selected from pharmaceutical additives and other substances generally used in the field in terms of applied doses or applied concentrations, and then used.

[0547] The anti-CDH6 antibody-drug conjugates of the present disclosure can be administered as a pharmaceutical composition comprising one or more pharmaceutically compatible components. For example, the pharmaceutical composition generally comprises one or more pharmaceutical carriers (e.g., a sterile liquid (e.g., water and oil (including petroleum oil and oils of animal origin, plant origin or synthetic origin (e.g., peanut oil, soybean oil, mineral oil and sesame oil))). When the pharmaceutical composition is administered intravenously, water is a more typical carrier. Aqueous saline solutions, aqueous glucose solutions and aqueous glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical vehicles are known in the art. If desired, the composition may also contain trace amounts of a wetting agent, an emulsifier or a pH buffer. Examples of suitable pharmaceutical carriers are disclosed in "Remington's Pharmaceutical Sciences" by EW Martin. The prescription corresponds to the mode of administration.

[0548] In some aspects, the antibody-drug conjugate (ADC) comprises formula 3. In some aspects, the ADC comprising formula 3 is administered to patients who show resistance to platinum-based cancer treatment. In some aspects, the ADC comprising formula 3 is administered to platinum-resistant cancer patients with cancer recurrence within 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months of completing platinum-based cancer treatment. In some aspects, the ADC comprising formula 3 is administered to platinum-resistant cancer patients with disease recurrence within at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months of completing platinum-based cancer treatment. In some aspects, the ADC comprising formula 3 is administered to platinum-resistant cancer patients with disease recurrence within at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months of completing carboplatin and / or paclitaxel regimens.

[0549] In some aspects, the ADC comprising Formula 3 is administered following treatment with platinum / taxane chemotherapy, such as carboplatin / docetaxel, cisplatin / paclitaxel, and carboplatin / paclitaxel / bevacizumab regimens.

[0550] In some aspects, an ADC comprising Formula 3 is administered after treatment with one or more of the following platinum-based chemotherapies, such as carboplatin / liposomal doxorubicin, carboplatin / gemcitabine, cisplatin / gemcitabine, carboplatin / ifosfamide, cisplatin / ifosfamide, oxaliplatin / 5-FU / leucovorin, and oxaliplatin / capecitabine regimens.

[0551] In some aspects, the ADC comprising Formula 3 is administered to patients in need for the treatment of platinum-resistant, preferably, ovarian cancer, non-small cell lung cancer (NSCLC), breast cancer, bladder cancer, endometrial cancer, castration-resistant prostate cancer (CRPC) and other cancers expressing CDH6 with disease recurrence. In some aspects, ovarian cancer includes epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer.

[0552] In some aspects, the ADC comprising Formula 3 is indicated for treating patients with ovarian cancer whose disease has progressed or relapsed after platinum-based chemotherapy. In some aspects, the ADC comprising Formula 3 is indicated for treating advanced ovarian cancer in women who have failed a first-line platinum-based chemotherapy regimen. In some aspects, the ADC comprising Formula 3 is indicated for treating ovarian cancer whose disease has progressed after chemotherapy.

[0553] In some aspects, the ADC comprising Formula 3 is indicated as a single agent for treating patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy. In some aspects, the ADC comprising Formula 3 is indicated for treating patients with metastatic ovarian cancer after failure of first-line or subsequent treatment.

[0554] Various delivery systems are known, and they can be used to administer the anti-CDH6 antibody-drug conjugates of the present disclosure. Examples of routes of administration may include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous routes. For example, administration may be by injection or bolus injection. According to a specific preferred embodiment, administration of the above-mentioned antibody-drug conjugate is performed by injection. Parenteral administration is a preferred route of administration.

[0555] According to representative embodiments, according to conventional procedures, the pharmaceutical composition is prescribed as a pharmaceutical composition suitable for intravenous administration to a human. Compositions for intravenous administration are generally solutions in sterile and isotonic aqueous buffer solutions. If necessary, the medicine may also contain a solubilizing agent and a local anesthetic to alleviate pain in the injection area (e.g., lidocaine). Typically, the above-mentioned components are provided together individually or in a mixture in a unit dosage form as a freeze-dried powder or anhydrous concentrate contained in a container, and the container is obtained by being sealed in an ampoule or a sachet (sachet) of, for example, the amount of an indicating active agent. When the medicine is to be administered by injection, an injection bottle containing, for example, sterile pharmaceutical grade water or saline may be used. When the medicine is to be administered by injection, an ampoule of sterile water for injection or saline may be provided so that the above-mentioned components are mixed with each other before administration.

[0556] The pharmaceutical composition of the present disclosure may be a pharmaceutical composition comprising only the anti-CDH6 antibody-drug conjugate of the present application, or may be a pharmaceutical composition comprising the anti-CDH6 antibody-drug conjugate and at least one other therapeutic agent for cancer. The anti-CDH6 antibody-drug conjugate of the present disclosure may also be administered together with an additional therapeutic agent for cancer, and the anti-cancer effect may be thereby enhanced. Additional anticancer agents for this purpose may be administered to an individual simultaneously, separately or continuously together with the antibody-drug conjugate. Otherwise, additional anticancer agents and anti-CDH6 antibody-drug conjugates may be administered to a subject at different administration intervals. In the present disclosure, the phrase "second drug" means a therapeutic agent other than the anti-CDH6 antibody-drug conjugate of the present disclosure. The additional anticancer agent may be a "second drug". However, in the present disclosure, the "second drug" is not necessarily a drug for the so-called "second-line therapy". Examples of therapeutic agents or second drugs or additional anticancer agents for this cancer may include tyrosine kinase inhibitors, including imatinib, sunitinib and regorafenib, CDK4 / 6 inhibitors, including palbociclib, HSP90 inhibitors, including TAS-116, MEK inhibitors, including MEK162, and immune checkpoint inhibitors, including nivolumab, pembrolizumab and ipilimumab, although the therapeutic agent for cancer is not limited thereto, as long as the drug has antitumor activity. In the case where the cancer is resistant to a specific anticancer agent, the second drug may be selected from an anticancer agent other than the specific therapeutic agent.

[0557] This pharmaceutical composition can be used as freeze-dried preparation or liquid preparation form, have the composition of selection and the preparation preparation of necessary purity.The pharmaceutical composition prepared as freeze-dried preparation can be the preparation containing the appropriate drug additives used in the described field.Similarly, liquid preparation can be prepared, thereby make the described liquid preparation contain the various drug additives used in the described field.

[0558] The composition and concentration of the pharmaceutical composition also vary depending on the method of administration. Regarding the affinity of the anti-CDH6 antibody-drug conjugate to the antigen contained in the pharmaceutical composition of the present disclosure, that is, the dissociation constant (Kd value) of the anti-CDH6 antibody-drug conjugate to the antigen, when the affinity increases (that is, the Kd value is low), even if its application dose is reduced, the pharmaceutical composition can also exert a medicinal effect. Therefore, the dosage of the application of the antibody-drug conjugate can also be determined by setting the dosage of the application based on the state of the affinity of the antibody-drug conjugate to the antigen. When the antibody-drug conjugate of the present disclosure is administered to a human, it can be administered once, for example, at a dose of about 0.001 to 100 mg / kg or multiple times at intervals of 1 to 180 days.

[0559] Treatments and uses The present disclosure provides methods of treating cancer comprising administering an anti-CDH6 antibody-drug conjugate as disclosed herein. Also provided herein is any disclosed anti-CDH6 ADC for use in treating cancer.

[0560] In some embodiments, the cancer is a cancer that expresses CDH6. Cancers that express CDH6 may include, but are not limited to, renal cell carcinoma, renal clear cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, thyroid cancer, bile duct cancer, lung cancer, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms tumor, and neuroblastoma.

[0561] For the purpose of the present disclosure, the term "cancer overexpressing CDH6" is not particularly limited as long as it is recognized by a person skilled in the art as a cancer overexpressing CDH6. Preferred examples of cancer overexpressing CDH6 may include cancers that give a high score of CDH6 expression in an immunohistochemical method (IHC) or an in situ hybridization method (ISH) or a next generation sequencing method (NGS). The in situ hybridization method of the present disclosure includes a fluorescent in situ hybridization method (FISH) and a dual color in situ hybridization method (DISH).

[0562] The method for scoring the degree of CDH6 expression by immunohistochemistry or the method for determining the positivity or negativity of CDH6 expression by in situ hybridization is not particularly limited as long as it is recognized by those skilled in the art.

[0563] In some embodiments, the ADC and the treatment methods and uses of the present disclosure can also be used as a pharmaceutical composition for treating cancer, which comprises the antibody-drug conjugate used in the present disclosure, its salt or their hydrate as an active ingredient, and a pharmaceutically acceptable formulation component.

[0564] In some embodiments, the ADC and treatment methods and uses of the present disclosure exhibit excellent anti-tumor activity against cancers that exhibit resistance to existing anti-cancer drugs (i.e., resistant cancers), particularly cancers that have acquired resistance to existing anti-cancer drugs (i.e., secondary resistant cancers). Therefore, the ADC for treatment of the present disclosure exerts a significant anti-tumor effect when applied to a patient group of cancer patients with cancers that are resistant to existing anti-cancer drugs (patients with a history of treatment with existing anti-cancer drugs). In particular, the cancer being treated may be resistant or refractory to treatment with platinum-based chemotherapy (i.e., cisplatin, carboplatin), chemotherapeutic agents (i.e., docetaxel, gemcitabine, liposomal doxorubicin, paclitaxel, topotecan), PARP inhibitor therapy (i.e., niraparib, olaparib, rucaparib, talazopanib), immune checkpoint inhibitor therapy (i.e., nivolumab, pembrolizumab, atezolizumab, avelumab, ipilimumab, durvalumab, tislelizumab, sintilimab, cemiplizumab), angiogenesis inhibitor therapy (i.e., bevacizumab, everolimus), and / or VEGFR-TKI therapy (i.e., pazopanib, sunitinib, sorafenib, cabozantinib, lenvatinib, axitinib).

[0565] The ADCs and methods of treatment and uses of the present disclosure may preferably be used to treat inoperable or recurrent cancers.

[0566] The ADC and treatment methods or uses of the present disclosure can delay the development of cancer cells, inhibit their growth and further kill cancer cells. These effects can allow cancer patients to get rid of the symptoms caused by cancer, or achieve an improvement in the quality of life (QOL) of cancer patients, and achieve a therapeutic effect by maintaining the life of cancer patients. Even if the anti-CDH6 antibody-drug conjugate of the present disclosure does not kill cancer cells, it can also provide a higher QOL for cancer patients while achieving longer-term survival by inhibiting or controlling the growth of cancer cells.

[0567] In some embodiments of the methods and uses, a subject having cancer (e.g., a cancer expressing CDH6) can be administered about 0.1 to about 15 mg / kg, about 0.5 to about 12 mg / kg, about 1.0 to about 10 mg / kg, or about 4 to about 8 mg / kg. In some embodiments, the dosage can be from about 1.0 mg / kg to about 12 mg / kg, from about 1.6 mg / kg to about 3.2 mg / kg, from about 1.6 mg / kg to about 4.8 mg / kg, from about 1.6 mg / kg to about 5.4 mg / kg, from about 1.6 mg / kg to about 5.6 mg / kg, from about 1.6 mg / kg to about 6.4 mg / kg, from about 1.6 mg / kg to about 8.0 mg / kg, from about 1.6 mg / kg to about 9.6 mg / kg, from about 3.2 mg / kg to about 4.8 mg / kg, from about 3.2 mg / kg to about 5.4 mg / kg, from about 3.2 mg / kg to about 5.6 mg / kg, from about 3.2 mg / kg to about 6.4 mg / kg, from about 3.2 mg / kg to about 8.0 mg / kg, from about 3.2 mg / kg to about 9.6 mg / kg. In some embodiments, the present invention relates to a device comprising: ...In some embodiments, the dose of the ADC administered to a subject can be about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8 , about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6. .1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, About 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, about 10.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.7, about 10.8, about 10.9, about 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, about 11.6, about 11.7, about 11.8, about 11.9 or about 12.0 mg / kg or more. In preferred embodiments, the dosage can be about 1.6 mg / kg, about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, or about 9.6 mg / kg, but more preferably about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, or about 9.6 mg / kg, but further preferably about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, or about 8.0 mg / kg, but further preferably about 4.8 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, or about 8.0 mg / kg.

[0568] In a preferred embodiment, the dosage can be about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5.0 mg / kg, about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 In some embodiments, the present invention relates to at least one embodiment of the present invention, wherein the present invention is preferably at least one embodiment of the present invention, but more preferably at least one embodiment of the present invention is at least one embodiment of the present invention.

[0569] In some embodiments of the methods and uses, a subject having cancer (eg, a cancer expressing CDH6) may be administered 0.1 to 15 mg / kg, 0.5 to 12 mg / kg, 1.0 to 10 mg / kg, or 4 to 8 mg / kg. In some embodiments, the dosage can be 1.0 mg / kg to 12 mg / kg, 1.6 mg / kg to 3.2 mg / kg, 1.6 mg / kg to 4.8 mg / kg, 1.6 mg / kg to 5.4 mg / kg, 1.6 mg / kg to 5.6 mg / kg, 1.6 mg / kg to 6.4 mg / kg, 1.6 mg / kg to 8.0 mg / kg, 1.6 mg / kg to 9.6 mg / kg, 3.2 mg / kg to 4.8 mg / kg, 3.2 mg / kg to 5.4 mg / kg, 3.2 mg / kg to 5.6 mg / kg, 3.2 mg / kg to 6.4 mg / kg, 3.2 mg / kg to 8.0 mg / kg, 3.2 mg / kg to 9.6 mg / kg, 4. 8mg / kg to 5.4mg / kg, 4.8mg / kg to 5.6mg / kg, 4.8mg / kg to 6.4mg / kg, 4.8mg / kg to 8.0mg / kg, 4.8mg / kg to 9.6mg / kg, 5.4mg / kg to 5.6mg / kg, 5.4mg / kg to 6.4mg / kg, 5.4mg / kg to 8.0mg / kg, 5.4mg / kg to 9.6mg / kg, 5.6mg / kg to 6.4mg / kg, 5.6mg / kg to 8.0mg / kg, 5.6mg / kg to 9.6mg / kg, 6.4mg / kg to 9.6mg / kg, 6.4mg / kg to 8.0mg / kg or 8.0mg / kg to 9.6mg / kg.In some embodiments, the dose of ADC administered to a subject can be 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2 .8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6. 1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4 , 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9 or 12.0 mg / kg or more. In a preferred embodiment, the dosage can be 1.6 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 6.4 mg / kg, 8.0 mg / kg, 9.6 mg / kg, but more preferably 3.2 mg / kg, 4.8 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 6.4 mg / kg, 8.0 mg / kg or 9.6 mg / kg, but further preferably 4.8 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 6.4 mg / kg or 8.0 mg / kg, but further preferably 4.8 mg / kg, 5.6 mg / kg, 6.4 mg / kg or 8.0 mg / kg.

[0570] In a preferred embodiment, the dosage can be 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6.0mg / kg, 6.1mg / kg, 6.2mg / kg, 6.3mg / kg or 6.4mg / kg, but more preferably 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg , 5.2mg / kg, 5.3mg / kg, 5.4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6.0mg / kg, 6.1mg / kg, 6.2mg / kg, 6.3mg / kg or 6.4mg / kg.

[0571] In some embodiments of the methods and uses, a subject having cancer (e.g., a cancer expressing CDH6) can be administered about 5 to 3000 mg, about 5 to 2500 mg, about 5 to 2000 mg, about 5 to about 1500 mg, about 5 to about 1000 mg, about 10 to about 3000 mg, about 10 to about 2500 mg, about 10 to about 2000 mg, about 10 to about 1500 mg, about 10 to about 1000 mg, about 25 to about 2500 mg, about 25 to about 2000 mg, about 25 to about 1500 mg, about 25 to about 1000 mg, about 50 to about 2500 mg, about 50 to about 2000 mg, about 50 to about 1500 mg, about 50 to about 1000 mg. , about 50 to about 950 mg, about 50 to about 900 mg, about 50 to about 850 mg, about 50 to about 800 mg, about 50 to about 750 mg, about 50 to about 700 mg, about 50 to about 650 mg, about 50 to about 600 mg, about 50 to about 550 mg, about 50 to about 500 mg, about 50 to about 450 mg, about 50 to about 400 mg, about 50 to about 350 mg, about 50 to about 300 mg, about 50 to about 250 mg, about 100 to about 2500 mg, about 100 to about 2000 mg, about 100 to about 1500 mg, about 100 to about 1000 mg, about 100 to about 950 mg, about 100 to about 900 mg, about 100 to about 85 0 mg, about 100 to about 800 mg, about 100 to about 750 mg, about 100 to about 700 mg, about 100 to about 650 mg, about 100 to about 600 mg, about 100 to about 550 mg, about 100 to about 500 mg, about 100 to about 450 mg, about 100 to about 400 mg, about 100 to about 350 mg, about 100 to about 300 mg, about 100 to about 250 mg, about 150 to about 2000 mg, about 150 to about 1500 mg, about 150 to about 1000 mg, about 150 to about 950 mg, about 150 to about 900 mg, about 150 to about 850 mg, about 150 to about 800 mg, about 150 to about 750 mg, about 150 to about 0 to about 700 mg, about 150 to about 650 mg, about 150 to about 600 mg, about 150 to about 550 mg, about 150 to about 500 mg, about 150 to about 450 mg, about 150 to about 400 mg, about 150 to about 350 mg, about 150 to about 300 mg, about 150 to about 250 mg, about 200 to about 1000 mg, about 200 to about 950 mg, about 200 to about 900 mg, about 200 to about 850 mg, about 200 to about 800 mg, about 200 to about 750 mg, about 200 to about 700 mg, about 200 to about 650 mg, about 200 to about 600 mg, about 200 to about 550 mg, about 200 to about 500 mg,about 200 to about 450 mg, about 200 to about 400 mg, about 200 to about 350 mg, about 200 to about 300 mg, about 200 to about 250 mg, about 250 to about 1000 mg, about 250 to about 950 mg, about 250 to about 900 mg, about 250 to about 850 mg, about 250 to about 800 mg, about 250 to about 750 mg, about 250 to about 700 mg, about 250 to about 650 mg, about 250 to about 600 mg, about 250 to about 550 mg, about 250 to about 500 mg, about 250 to about 450 mg, about 250 to about 400 mg, about 250 to about 350 mg, about 250 to about 300 mg, about 300 to about 1000 mg, about 300 to about 950 mg, about 300 to about 900 mg, about 300 to about 850 mg, about 300 to about 800 mg, about 300 to about 750 mg, about 300 to about 700 mg, about 300 to about 650 mg, about 300 to about 600 mg, about 300 to about 550 mg, about 300 to about 500 mg, about 300 to about 450 mg, about 300 to about 400 mg, about 300 to about 350 mg, about 350 to about 1000 mg, about 350 to about 950 mg, about 350 to about 900 mg, about 350 to about 850 mg, about 350 to about 800 mg, about 350 to about 750 mg, about 350 to about 700 mg, about 350 to about 650 mg, about 350 to about 600 mg, about 350 to about 550 mg, about 350 to about 500 mg, about 350 to about 450 mg, about 350 to about 400 mg, about 400 to about 1000 mg, about 400 to about 950 mg, about 400 to about 900 mg, about 400 to about 850 mg, about 400 to about 800 mg, about 400 to about 750 mg, about 400 to about 700 mg, about 400 to about 650 mg, about 400 to about 600 mg, about 400 to about 550 mg, about 400 to about 500 mg, about 400 to about 450 mg, about 450 to about 1000 mg In other words, in some embodiments, the dose of ADC administered to a subject may be about 5 mg, about 500 to about 950 mg, about 500 to about 900 mg, about 500 to about 850 mg, about 500 to about 800 mg, about 500 to about 750 mg, about 500 to about 700 mg, about 500 to about 650 mg, about 500 to about 600 mg, about 450 to about 550 mg, about 450 to about 500 mg, about 500 to about 1000 mg, about 500 to about 950 mg, about 500 to about 900 mg, about 500 to about 850 mg, about 500 to about 800 mg, about 500 to about 750 mg, about 500 to about 700 mg, about 500 to about 650 mg, about 500 to about 600 mg, or about 500 to about 550 mg.about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg, about 435mg, about 440mg, about 445mg, about 450mg, about 455mg g, about 460mg, about 465mg, about 470mg, about 475mg, about 480mg, about 485mg, about 490mg, about 495mg, about 500mg, about 505mg, about 510mg, about 515mg, about 520mg, about 525mg, about 530mg, about 535mg, about 540mg, about 545mg, about 550mg, about 555mg, about 560mg, about 565mg, about 570mg, about 575mg, about 580mg, about 585mg, about 590mg, about 595mg, about 600mg, about 605mg, about 610mg, about 615mg, about 620mg, about 625mg, about 630mg, about 6 35mg, about 640mg, about 645mg, about 650mg, about 655mg, about 660mg, about 665mg, about 670mg, about 675mg, about 680mg, about 685mg, about 690mg, about 695mg, about 700mg, about 705mg, about 710mg, about 715mg, about 720mg, about 725mg, about 730mg, about 735mg, about 740mg, about 745mg, about 750mg, about 755mg, about 760mg, about 765mg, about 770mg, about 775mg, about 780mg, about 785mg, about 790mg, about 795mg, about 800mg, about 805mg, about 810mg,about 815mg, about 820mg, about 825mg, about 830mg, about 835mg, about 840mg, about 845mg, about 850mg, about 855mg, about 860mg, about 865mg, about 870mg, about 875mg, about 880mg, about 885mg, about 890mg, about 895mg, about 900mg, about 905mg, about 910mg, about 915mg, about 9 20mg, about 925mg, about 930mg, about 935mg, about 940mg, about 945mg, about 950mg, about 955mg, about 960mg, about 965mg, about 970mg, about 975mg, about 980mg, about 985mg, about 990mg, about 995mg, about 1000mg, about 1025mg, about 1050mg, about 1075mg, about 1100mg , about 1125mg, about 1150mg, about 1175mg, about 1200mg, about 1225mg, about 1250mg, about 1275mg, about 1300mg, about 1325mg, about 1350mg, about 1375mg, about 1400mg, about 1425mg, about 1450mg, about 1475mg, about 1500mg, about 1525mg, about 1550mg, about 157 5 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg or about 2000 mg or any value therebetween.

[0572] In preferred embodiments, the dose of ADC administered to a subject can be about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about about 360mg, about 365mg, about 370mg, about 375mg, about 380mg, about 385mg, about 390mg, about 395mg, about 400mg, about 405mg, about 410mg, about 415mg, about 420mg, about 425mg, about 430mg, about 435mg, about 440mg, about 445mg, about 450mg, about 455mg, about 460mg, about 465mg, about 470mg, about 475mg, about 480mg, about 485mg, about 490mg, about 495mg, about 500mg, about 505mg, about 510mg, about 515mg, about 520mg, about 525mg, about 530mg, about 535mg g, about 540mg, about 545mg, about 550mg, about 555mg, about 560mg, about 565mg, about 570mg, about 575mg, about 580mg, about 585mg, about 590mg, about 595mg, about 600mg, about 605mg, about 610mg, about 615mg, about 620mg, about 625mg, about 630mg, about 635mg, about 640mg, about 645mg, about 650mg, about 655mg, about 660mg, about 665mg, about 670mg, about 675mg, about 680mg, about 685mg, about 690mg, about 695mg, about 700mg, about 705mg, about 710mg, about 7 15mg, about 720mg, about 725mg, about 730mg, about 735mg, about 740mg, about 745mg, about 750mg, about 755mg, about 760mg, about 765mg, about 770mg, about 775mg, about 780mg, about 785mg, about 790mg, about 795mg, about 800mg, about 805mg, about 810mg, about 815mg, about 820mg, about 825mg, about 830mg, about 835mg, about 840mg, about 845mg, about 850mg, about 855mg, about 860mg, about 865mg, about 870mg, about 875mg, about 880mg, about 885mg, about 890mg,about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg or about 1000 mg.

[0573] In some embodiments of the methods and uses, a subject having cancer (e.g., a cancer expressing CDH6) can be administered 5 to 3000 mg, 5 to 2500 mg, 5 to 2000 mg, 5 to 1500 mg, 5 to 1000 mg, 10 to 3000 mg, 10 to 2500 mg, 10 to 2000 mg, 10 to 1500 mg, 10 to 1000 mg, 25 to 2500 mg, 25 to 2000 mg, 25 to 1500 mg, 25 to 1000 mg, 50 to 2500 mg, 50 to 2000 mg, 50 to 1500 mg, 50 to 1000 mg, 50 to 950 mg, 50 to 900 mg, 50 to 850 mg, 50 to 800mg, 50 to 750mg, 50 to 700mg, 50 to 650mg, 50 to 600mg, 50 to 550mg, 50 to 500mg, 50 to 450mg, 50 to 400mg, 50 to 350mg, 50 to 300mg, 50 to 250mg, 100 to 2500mg, 100 to 2000mg, 100 to 1500mg, 100 to 1000mg, 100 to 950mg, 100 to 900mg, 100 to 850mg, 100 to 800mg, 100 to 750mg, 100 to 700mg, 100 to 650mg, 100 to 600mg, 100 to 550mg, 100 to 500mg , 100 to 450mg, 100 to 400mg, 100 to 350mg, 100 to 300mg, 100 to 250mg, 150 to 2000mg, 150 to 1500mg, 150 to 1000mg, 150 to 950mg, 150 to 900mg, 150 to 850mg, 150 to 800mg, 150 to 750mg, 150 to 700mg, 150 to 650mg, 150 to 600mg, 150 to 550mg, 150 to 500mg, 150 to 450mg, 150 to 400mg, 150 to 350mg, 150 to 300mg, 150 to 250mg, 200 to 1000mg, 200 to 950mg, 200 to 900mg, 200 to 850mg, 200 to 800mg, 200 to 750mg, 200 to 700mg, 200 to 650mg, 200 to 600mg, 200 to 550mg, 200 to 500mg, 200 to 450mg, 200 to 400mg, 200 to 350mg, 200 to 300mg, 200 to 250mg, 250 to 1000mg, 250 to 950mg, 250 to 900mg, 250 to 850mg, 250 to 800mg, 250 to 750mg, 250 to 700mg, 250 to 650mg, 250 to 600mg, 250 to 550mg,250 to 500 mg, 250 to 450 mg, 250 to 400 mg, 250 to 350 mg, 250 to 300 mg, 300 to 1000 mg, 300 to 950 mg, 300 to 900 mg, 300 to 850 mg, 300 to 800 mg, 300 to 750 mg, 300 to 700 mg, 300 to 650 mg, 300 to 600 mg, 300 to 550 mg, 300 to 500 mg, 300 to 950 mg, 300 to 900 mg, 300 to 850 mg, 300 to 800 mg, 300 to 750 mg, 300 to 700 mg, 300 to 650 mg, 300 to 600 mg, 300 to 550 mg, 300 to 500 mg, 300 to 0 to 450 mg, 300 to 400 mg, 300 to 350 mg, 350 to 1000 mg, 350 to 950 mg, 350 to 900 mg, 350 to 850 mg, 350 to 800 mg, 350 to 750 mg, 350 to 700 mg, 350 to 650 mg, 350 to 600 mg, 350 to 550 mg, 350 to 500 mg, 350 to 450 mg, 350 to 400 mg, 400 to 1 000mg, 400 to 950mg, 400 to 900mg, 400 to 850mg, 400 to 800mg, 400 to 750mg, 400 to 700mg, 400 to 650mg, 400 to 600mg, 400 to 550mg, 400 to 500mg, 400 to 450mg, 450 to 1000mg, 450 to 950mg, 450 to 900mg, 450 to 850mg, 450 to 800mg In some embodiments, the present invention relates to an oral dosage form of at least 200 mg ... In other words, in some embodiments, the dose of ADC administered to a subject can be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 20mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290 mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg,365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg、605mg、610mg、615mg、620mg、625mg、630mg、635mg、640mg、645mg、650mg、655mg、660mg、665mg、670mg、675mg、680mg、685mg、690mg、695mg、700mg、705mg、710mg、715mg、720mg、725mg、730mg、735mg、740mg、745mg、750mg、755mg、760mg、765mg、770mg、775mg、780mg、785mg、790mg、795mg、800mg、805mg、810mg、815mg、820mg、825mg、830mg、835mg、840mg、845mg、850mg、855mg、860mg、865mg、870mg、875mg、880mg、885mg、890mg、895mg、900mg、905mg、910mg、915mg、920mg、925mg、930mg、935mg、940mg、945mg、950mg、955mg、960mg、965mg、970mg、975mg、980mg、985mg、990mg、995mg、1000mg、1025mg、1050mg、1075mg、1100mg、1125mg、1150mg、1175mg、1200mg、1225mg、1250mg、1275mg、1300mg、1325mg、1350mg、1375mg、1400mg、1425mg、1450mg、1475mg、1500mg、1525mg、1550mg、1575mg、1600mg、1625mg、1650mg、1675mg、1700mg、1725mg、1750mg、1775mg、1800mg、1825mg、1850mg, 1875mg, 1900mg, 1925mg, 1950mg, 1975mg or 2000mg or any value therebetween.

[0574] In a preferred embodiment, the dose of ADC administered to a subject can be 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 490 mg, 495 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 715 mg, 720 mg, 730 mg, 740 mg 85mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg , 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590 mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 650mg, 655mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 6 95mg, 700mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755mg, 760mg, 765mg, 770mg, 775mg, 780mg, 785mg, 790mg, 795mg , 800mg, 805mg, 810mg, 815mg, 820mg, 825mg, 830mg, 835mg, 840mg, 845mg, 850mg, 855mg, 860mg, 865mg, 870mg, 875mg, 880mg, 885mg, 890mg, 895mg, 900mg, 905mg, 910mg, 915mg, 920mg, 925mg, 930mg, 935mg, 940mg, 945mg, 950mg, 955mg, 960mg, 965mg, 970mg, 975mg, 980mg, 985mg, 990mg, 995mg or 1000mg.

[0575] In some embodiments of the methods and uses, the anti-CDH6 ADC or its pharmaceutical composition is administered to a subject suffering from cancer via parenteral administration. Preferred parenteral administration routes include, but are not limited to, injections, such as intravenous, intramuscular, and subcutaneous injections. It is expected that the anti-CDH6 antibody-drug conjugates used in the present disclosure exert therapeutic effects by application to patients as systemic therapy and additionally by local application to cancer tissues.

[0576] The timing or schedule of administration may be once every 1 week (q1w), once every 2 weeks (q2w), once every 3 weeks (q3w), once every 4 weeks (q4w), once every 5 weeks (q5w), once every 6 weeks (q6w), once every 7 weeks (q7w), once every 8 weeks (q8w), once every 9 weeks (q9w) or once every 10 weeks (q10w), but preferably once every 3 or 4 weeks, but more preferably once every 3 weeks.

[0577] The dosage regimen can be adjusted to provide the best desired response (e.g., a therapeutic response, such as tumor regression or remission). The following dosage is shown for once every three weeks, but can also be provided q1w, q2w, q4w, q5w, q6w, q7w, q8w, q9w, or q10w. For example, in some embodiments, the dosage regimen can be 0.1 mg / kg once every 3 weeks (q3w), 0.2 mg / kg once every 3 weeks (q3w), 0.3 mg / kg once every 3 weeks (q3w), 0.4 mg / kg once every 3 weeks (q3w), 0.5 mg / kg once every 3 weeks (q3w), 0.6 mg / kg once every 3 weeks (q3w), 0.7 mg / kg once every 3 weeks (q3w), 0.8 mg / kg once every 3 weeks (q3w), 0.9 mg / kg once every 3 weeks (q3w), 1.0 mg / kg once every 3 weeks (q3w), 1.1 mg / kg once every 3 weeks (q3w), q3w), 1.2mg / kg once every 3 weeks (q3w), 1.3mg / kg once every 3 weeks (q3w), 1.4mg / kg once every 3 weeks (q3w), 1.5mg / kg once every 3 weeks (q3w), 1.6mg / kg once every 3 weeks (q3w), 1.7mg / kg once every 3 weeks (q3w), 1.8mg / kg once every 3 weeks (q3w), 1.9mg / kg once every 3 weeks (q3w), 2.0mg / kg once every 3 weeks (q3w), 2.1mg / kg once every 3 weeks (q3w), 2.2mg / kg once every 3 weeks (q3w), 2.3mg / kg once every 3 weeks (q3w). once a week (q3w), 2.4mg / kg once every 3 weeks (q3w), 2.5mg / kg once every 3 weeks (q3w), 2.6mg / kg once every 3 weeks (q3w), 2.7mg / kg once every 3 weeks (q3w), 2.8mg / kg once every 3 weeks (q3w), 2.9mg / kg once every 3 weeks (q3w), 3.0mg / kg once every 3 weeks (q3w), 3.1mg / kg once every 3 weeks (q3w), 3.2mg / kg once every 3 weeks (q3w), 3.3mg / kg once every 3 weeks (q3w), 3.4mg / kg once every 3 weeks (q3w), 3.5mg / kg kg once every 3 weeks (q3w), 3.6mg / kg once every 3 weeks (q3w), 3.7mg / kg once every 3 weeks (q3w), 3.8mg / kg once every 3 weeks (q3w), 3.9mg / kg once every 3 weeks (q3w), 4.0mg / kg once every 3 weeks (q3w), 4.1mg / kg once every 3 weeks (q3w), 4.2mg / kg once every 3 weeks (q3w), 4.3mg / kg once every 3 weeks (q3w), 4.4mg / kg once every 3 weeks (q3w), 4.5mg / kg once every 3 weeks (q3w), 4.6mg / kg once every 3 weeks (q3w), 4.7mg / kg once every 3 weeks (q3w), 4.8mg / kg once every 3 weeks (q3w), 4.9mg / kg once every 3 weeks (q3w), 5.0mg / kg once every 3 weeks (q3w), 5.1mg / kg once every 3 weeks (q3w), 5.2mg / kg once every 3 weeks (q3w), 5.3mg / kg once every 3 weeks (q3w), 5.4mg / kg once every 3 weeks (q3w), 5.5mg / kg once every 3 weeks (q3w), 5.6mg / kg once every 3 weeks (q3w), 5.7mg / kg once every 3 weeks (q3w), 5.8mg / kg once every 3 weeks (q3w), 5.9mg / kg once every 3 weeks (q3w), 6. 0mg / kg once every 3 weeks (q3w), 6.1mg / kg once every 3 weeks (q3w), 6.2mg / kg once every 3 weeks (q3w), 6.3mg / kg once every 3 weeks (q3w), 6.4mg / kg once every 3 weeks (q3w), 6.5mg / kg once every 3 weeks (q3w), 6.6mg / kg once every 3 weeks (q3w), 6.7mg / kg once every 3 weeks (q3w), 6.8mg / kg once every 3 weeks (q3w), 6.9mg / kg once every 3 weeks (q3w), 7.0mg / kg once every 3 weeks (q3w), 7.1mg / kg once every 3 weeks (q3w), 7.2mg / kg once every 3 weeks (q3w), 7. 3mg / kg once every 3 weeks (q3w), 7.4mg / kg once every 3 weeks (q3w), 7.5mg / kg once every 3 weeks (q3w), 7.6mg / kg once every 3 weeks (q3w), 7.7mg / kg once every 3 weeks (q3w), 7.8mg / kg once every 3 weeks (q3w), 7.9mg / kg once every 3 weeks (q3w), 8.0mg / kg once every 3 weeks (q3w), 8.1mg / kg once every 3 weeks (q3w), 8.2mg / kg once every 3 weeks (q3w), 8.3mg / kg once every 3 weeks (q3w), 8.4mg / kg once every 3 weeks (q3w), 8.5mg / kg once every 3 weeks (q3w), 8. 6mg / kg once every 3 weeks (q3w), 8.7mg / kg once every 3 weeks (q3w), 8.8mg / kg once every 3 weeks (q3w), 8.9mg / kg once every 3 weeks (q3w), 9.0mg / kg once every 3 weeks (q3w), 9.1mg / kg once every 3 weeks (q3w), 9.2mg / kg once every 3 weeks (q3w), 9.3mg / kg once every 3 weeks (q3w), 9.4mg / kg once every 3 weeks (q3w), 9.5mg / kg once every 3 weeks (q3w), 9.6mg / kg once every 3 weeks (q3w), 9.7mg / kg once every 3 weeks (q3w), 9.8mg / kg once every 3 weeks (q3w), 9.9mg / kg once every 3 weeks (q3w), 10.0mg / kg once every 3 weeks (q3w), 10.1mg / kg once every 3 weeks (q3w), 10.2mg / kg once every 3 weeks (q3w), 10.3mg / kg once every 3 weeks (q3w), 10.4mg / kg once every 3 weeks (q3w), 10.5mg / kg once every 3 weeks (q3w), 10.6mg / kg once every 3 weeks (q3w), 10.7mg / kg once every 3 weeks (q3w), 10.8mg / kg once every 3 weeks (q3w), 10.9mg / kg once every 3 weeks (q3w), 1 1.0 mg / kg once every 3 weeks (q3w), 11.1 mg / kg once every 3 weeks (q3w), 11.2 mg / kg once every 3 weeks (q3w), 11.3 mg / kg once every 3 weeks (q3w), 11.4 mg / kg once every 3 weeks (q3w), 11.5 mg / kg once every 3 weeks (q3w), 11.6 mg / kg once every 3 weeks (q3w), 11.7 mg / kg once every 3 weeks (q3w), 11.8 mg / kg once every 3 weeks (q3w), 11.9 mg / kg once every 3 weeks (q3w) or 12.0 mg / kg once every 3 weeks (q3w). In a preferred embodiment, the dosage regimen may be 1.6 mg / kg once every 3 weeks (q3w), 3.2 mg / kg once every 3 weeks (q3w), 4.8 mg / kg once every 3 weeks (q3w), 6.4 mg / kg once every 3 weeks (q3w), 8.0 mg / kg once every 3 weeks (q3w), 9.6 mg / kg once every 3 weeks (q3w), but more preferably 3.2 mg / kg once every 3 weeks (q3w), 4.8 mg / kg once every 3 weeks (q3w), 6.4 mg / kg once every 3 weeks (q3w), 8.0 mg / kg once every 3 weeks (q3w), or 9.6 mg / kg once every 3 weeks (q3w), but further preferably 6.4 mg / kg once every 3 weeks (q3w) or 8.0 mg / kg once every 3 weeks (q3w), but further preferably 8.0 mg / kg once every 3 weeks (q3w). .

[0578] In a preferred embodiment, the dosage regimen can be 3.2 mg / kg once every 3 weeks (q3w), 3.3 mg / kg once every 3 weeks (q3w), 3.4 mg / kg once every 3 weeks (q3w), 3.5 mg / kg once every 3 weeks (q3w), 3.6 mg / kg once every 3 weeks (q3w), 3.7 mg / kg once every 3 weeks (q3w), 3.8 mg / kg once every 3 weeks (q3w), 3.9 mg / kg once every 3 weeks (q3w), 4.0 mg / kg once every 3 weeks (q3w), 4.1 mg / kg once every 3 weeks (q3w), 4.2 mg / kg once every 3 weeks (q3w), 4.3 mg / kg once every 3 weeks (q3w). w), 4.4mg / kg once every 3 weeks (q3w), 4.5mg / kg once every 3 weeks (q3w), 4.6mg / kg once every 3 weeks (q3w), 4.7mg / kg once every 3 weeks (q3w), 4.8mg / kg once every 3 weeks (q3w), 4.9mg / kg once every 3 weeks (q3w), 5.0mg / kg once every 3 weeks (q3w), 5.1mg / kg once every 3 weeks (q3w), 5.2mg / kg once every 3 weeks (q3w), 5.3mg / kg once every 3 weeks (q3w), 5.4mg / kg once every 3 weeks (q3w), 5.5mg / kg once every 3 weeks (q3w), 5.6mg / kg once every 3 weeks times (q3w), 5.7mg / kg once every 3 weeks (q3w), 5.8mg / kg once every 3 weeks (q3w), 5.9mg / kg once every 3 weeks (q3w), 6.0mg / kg once every 3 weeks (q3w), 6.1mg / kg once every 3 weeks (q3w), 6.2mg / kg once every 3 weeks (q3w), 6.3mg / kg once every 3 weeks (q3w) or 6.4mg / kg once every 3 weeks (q3w), but more preferably 4.8mg / kg once every 3 weeks (q3w), 4.9mg / kg once every 3 weeks (q3w), 5.0mg / kg once every 3 weeks (q3w), 5.1mg / kg once every 3 weeks (q3w), 5.2mg / kg once every 3 weeks (q3w) g / kg once every 3 weeks (q3w), 5.3mg / kg once every 3 weeks (q3w), 5.4mg / kg once every 3 weeks (q3w), 5.5mg / kg once every 3 weeks (q3w), 5.6mg / kg once every 3 weeks (q3w), 5.7mg / kg once every 3 weeks (q3w), 5.8mg / kg once every 3 weeks (q3w), 5.9mg / kg once every 3 weeks (q3w), 6.0mg / kg once every 3 weeks (q3w), 6.1mg / kg once every 3 weeks (q3w), 6.2mg / kg once every 3 weeks (q3w), 6.3mg / kg once every 3 weeks (q3w), or 6.4mg / kg once every 3 weeks (q3w). In some embodiments, the dosage regimen can be 5mg once every 3 weeks (q3w),10 mg once every 3 weeks (q3w), 15 mg once every 3 weeks (q3w), 20 mg once every 3 weeks (q3w), 25 mg once every 3 weeks (q3w), 30 mg once every 3 weeks (q3w), 35 mg once every 3 weeks (q3w), 40 mg once every 3 weeks (q3w), 45 mg once every 3 weeks (q3w), 50 mg once every 3 weeks (q3w), 55 mg once every 3 weeks (q3w), 60 mg once every 3 weeks (q3w), 65 mg once every 3 weeks (q3w), 70 mg once every 3 weeks (q3w), 75 mg once every 3 weeks (q3w), 80 mg once every 3 weeks (q3w), 85 mg once every 3 weeks (q3w), 90 mg once every 3 weeks once (q3w), 95mg once every 3 weeks (q3w), 100mg once every 3 weeks (q3w), 125mg once every 3 weeks (q3w), 150mg once every 3 weeks (q3w), 175mg once every 3 weeks (q3w), 200mg once every 3 weeks (q3w), 205mg once every 3 weeks (q3w), 210mg once every 3 weeks (q3w), 215mg once every 3 weeks (q3w), 220mg once every 3 weeks (q3w), 225mg once every 3 weeks (q3w), 230mg once every 3 weeks (q3w), 235mg once every 3 weeks (q3w), 240mg once every 3 weeks (q3w), 245mg once every 3 weeks (q3w), 2 50 mg once every 3 weeks (q3w), 255 mg once every 3 weeks (q3w), 260 mg once every 3 weeks (q3w), 265 mg once every 3 weeks (q3w), 270 mg once every 3 weeks (q3w), 275 mg once every 3 weeks (q3w), 280 mg once every 3 weeks (q3w), 285 mg once every 3 weeks (q3w), 290 mg once every 3 weeks (q3w), 295 mg once every 3 weeks (q3w), 300 mg once every 3 weeks (q3w), 305 mg once every 3 weeks (q3w), 310 mg once every 3 weeks (q3w), 315 mg once every 3 weeks (q3w), 320 mg once every 3 weeks (q3w), 325 mg once every 3 weeks once (q3w), 330mg once every 3 weeks (q3w), 335mg once every 3 weeks (q3w), 340mg once every 3 weeks (q3w), 345mg once every 3 weeks (q3w), 350mg once every 3 weeks (q3w), 355mg once every 3 weeks (q3w), 360mg once every 3 weeks (q3w), 365mg once every 3 weeks (q3w), 370mg once every 3 weeks (q3w), 375mg once every 3 weeks (q3w), 380mg once every 3 weeks (q3w), 385mg once every 3 weeks (q3w), 390mg once every 3 weeks (q3w), 395mg once every 3 weeks (q3w), 400mg once every 3 weeks (q3w),405 mg once every 3 weeks (q3w), 410 mg once every 3 weeks (q3w), 415 mg once every 3 weeks (q3w), 420 mg once every 3 weeks (q3w), 425 mg once every 3 weeks (q3w), 430 mg once every 3 weeks (q3w), 435 mg once every 3 weeks (q3w), 440 mg once every 3 weeks (q3w), 445 mg once every 3 weeks (q3w), 450 mg once every 3 weeks (q3w), 455 mg once every 3 weeks (q3w), 460 mg once every 3 weeks (q3w), 465 mg once every 3 weeks (q3w), 470 mg once every 3 weeks (q3w), 475 mg once every 3 weeks (q3w), 480 mg once every 3 weeks once (q3w), 485mg once every 3 weeks (q3w), 490mg once every 3 weeks (q3w), 495mg once every 3 weeks (q3w), 500mg once every 3 weeks (q3w), 505mg once every 3 weeks (q3w), 510mg once every 3 weeks (q3w), 515mg once every 3 weeks (q3w), 520mg once every 3 weeks (q3w), 525mg once every 3 weeks (q3w), 530mg once every 3 weeks (q3w), 535mg once every 3 weeks (q3w), 540mg once every 3 weeks (q3w), 545mg once every 3 weeks (q3w), 550mg once every 3 weeks (q3w), 555mg once every 3 weeks (q3w), 560 mg once every 3 weeks (q3w), 565 mg once every 3 weeks (q3w), 570 mg once every 3 weeks (q3w), 575 mg once every 3 weeks (q3w), 580 mg once every 3 weeks (q3w), 585 mg once every 3 weeks (q3w), 590 mg once every 3 weeks (q3w), 595 mg once every 3 weeks (q3w), 600 mg once every 3 weeks (q3w), 605 mg once every 3 weeks (q3w), 610 mg once every 3 weeks (q3w), 615 mg once every 3 weeks (q3w), 620 mg once every 3 weeks (q3w), 625 mg once every 3 weeks (q3w), 630 mg once every 3 weeks (q3w), 635 mg once every 3 weeks once (q3w), 640mg once every 3 weeks (q3w), 645mg once every 3 weeks (q3w), 650mg once every 3 weeks (q3w), 655mg once every 3 weeks (q3w), 660mg once every 3 weeks (q3w), 665mg once every 3 weeks (q3w), 670mg once every 3 weeks (q3w), 675mg once every 3 weeks (q3w), 680mg once every 3 weeks (q3w), 685mg once every 3 weeks (q3w), 690mg once every 3 weeks (q3w), 695mg once every 3 weeks (q3w), 700mg once every 3 weeks (q3w), 705mg once every 3 weeks (q3w), 710mg once every 3 weeks (q3w),715 mg once every 3 weeks (q3w), 720 mg once every 3 weeks (q3w), 725 mg once every 3 weeks (q3w), 730 mg once every 3 weeks (q3w), 735 mg once every 3 weeks (q3w), 740 mg once every 3 weeks (q3w), 745 mg once every 3 weeks (q3w), 750 mg once every 3 weeks (q3w), 755 mg once every 3 weeks (q3w), 760 mg once every 3 weeks (q3w), 765 mg once every 3 weeks (q3w), 770 mg once every 3 weeks (q3w), 775 mg once every 3 weeks (q3w), 780 mg once every 3 weeks (q3w), 785 mg once every 3 weeks (q3w), 790 mg once every 3 weeks once every 3 weeks (q3w), 795 mg once every 3 weeks (q3w), 800 mg once every 3 weeks (q3w), 805 mg once every 3 weeks (q3w), 810 mg once every 3 weeks (q3w), 815 mg once every 3 weeks (q3w), 820 mg once every 3 weeks (q3w), 825 mg once every 3 weeks (q3w), 830 mg once every 3 weeks (q3w), 835 mg once every 3 weeks (q3w), 840 mg once every 3 weeks (q3w), 845 mg once every 3 weeks (q3w), 850 mg once every 3 weeks (q3w), 855 mg once every 3 weeks (q3w), 860 mg once every 3 weeks (q3w), 865 mg once every 3 weeks (q3w), 87 0mg once every 3 weeks (q3w), 875mg once every 3 weeks (q3w), 880mg once every 3 weeks (q3w), 885mg once every 3 weeks (q3w), 890mg once every 3 weeks (q3w), 895mg once every 3 weeks (q3w), 900mg once every 3 weeks (q3w), 905mg once every 3 weeks (q3w), 910mg once every 3 weeks (q3w), 915mg once every 3 weeks (q3w), 920mg once every 3 weeks (q3w), 925mg once every 3 weeks (q3w), 930mg once every 3 weeks (q3w), 935mg once every 3 weeks (q3w), 940mg once every 3 weeks (q3w), 945mg once every 3 weeks (q3w) q3w), 950mg once every 3 weeks (q3w), 955mg once every 3 weeks (q3w), 960mg once every 3 weeks (q3w), 965mg once every 3 weeks (q3w), 970mg once every 3 weeks (q3w), 975mg once every 3 weeks (q3w), 980mg once every 3 weeks (q3w), 985mg once every 3 weeks (q3w), 990mg once every 3 weeks (q3w), 995mg once every 3 weeks (q3w), 1000mg once every 3 weeks (q3w), 1025mg once every 3 weeks (q3w), 1050mg once every 3 weeks (q3w), 1075mg once every 3 weeks (q3w), 1100mg once every 3 weeks (q3w),1125 mg once every 3 weeks (q3w), 1150 mg once every 3 weeks (q3w), 1175 mg once every 3 weeks (q3w), 1200 mg once every 3 weeks (q3w), 1225 mg once every 3 weeks (q3w), 1250 mg once every 3 weeks (q3w), 1275 mg once every 3 weeks (q3w), 1300 mg once every 3 weeks (q3w), 1325 mg once every 3 weeks (q3w), 1350 mg once every 3 weeks (q3w), 1375 mg once every 3 weeks (q3w), 1400 mg once every 3 weeks (q3w), 1425 mg once every 3 weeks (q3w), 1450 mg once every 3 weeks (q3w), 1475 mg once every 3 weeks (q3w), 1500 mg once every 3 weeks (q3w), 1525 mg once every 3 weeks (q3w), 1550 mg once every 3 weeks (q3w), 1575 mg once every 3 weeks (q3w), 1600 mg once every 3 weeks (q3w), 1625 mg once every 3 weeks (q3w), 1650 mg once every 3 weeks (q3w), 1675 mg once every 3 weeks (q3w), 1700 mg once every 3 weeks (q3w), 1725 mg once every 3 weeks (q3w), 1750 mg once every 3 weeks (q3w), 1775 mg once every 3 weeks (q3w), 1800 mg once every 3 weeks (q3w), 1825 mg once every 3 weeks (q3w), 1850 mg once every 3 weeks (q3w), 1875 mg once every 3 weeks (q3w), 1900 mg once every 3 weeks (q3w), 1925 mg once every 3 weeks (q3w), 1950 mg once every 3 weeks (q3w), 1975 mg once every 3 weeks (q3w) or 2000 mg once every 3 weeks (q3w). In a preferred embodiment, the dosage regimen can be 200 mg once every 3 weeks (q3w), 205 mg once every 3 weeks (q3w), 210 mg once every 3 weeks (q3w), 215 mg once every 3 weeks (q3w), 220 mg once every 3 weeks (q3w), 225 mg once every 3 weeks (q3w), 230 mg once every 3 weeks (q3w), 235 mg once every 3 weeks (q3w), 240 mg once every 3 weeks (q3w), 245 mg once every 3 weeks (q3w), 250 mg once every 3 weeks (q3w), 255 mg once every 3 weeks (q3w), 260 mg once every 3 weeks (q3w), 265 mg once every 3 weeks (q3w), 270 mg once every 3 weeks (q3w), 275 mg once every 3 weeks (q3w), 280 mg once every 3 weeks (q3w), 285 mg once every 3 weeks (q3w), 290 mg once every 3 weeks (q3w), 295 mg once every 3 weeks (q3w), 300 mg once every 3 weeks (q3w), 305 mg once every 3 weeks (q3w), 310 mg once every 3 weeks (q3w),315 mg once every 3 weeks (q3w), 320 mg once every 3 weeks (q3w), 325 mg once every 3 weeks (q3w), 330 mg once every 3 weeks (q3w), 335 mg once every 3 weeks (q3w), 340 mg once every 3 weeks (q3w), 345 mg once every 3 weeks (q3w), 350 mg once every 3 weeks (q3w), 355 mg once every 3 weeks (q3w), 360 mg once every 3 weeks (q3w), 365 mg once every 3 weeks (q3w), 370 mg once every 3 weeks (q3w), 375 mg once every 3 weeks (q3w), 380 mg once every 3 weeks (q3w), 385 mg once every 3 weeks (q3w), 390 mg once every 3 weeks once (q3w), 395mg once every 3 weeks (q3w), 400mg once every 3 weeks (q3w), 405mg once every 3 weeks (q3w), 410mg once every 3 weeks (q3w), 415mg once every 3 weeks (q3w), 420mg once every 3 weeks (q3w), 425mg once every 3 weeks (q3w), 430mg once every 3 weeks (q3w), 435mg once every 3 weeks (q3w), 440mg once every 3 weeks (q3w), 445mg once every 3 weeks (q3w), 450mg once every 3 weeks (q3w), 455mg once every 3 weeks (q3w), 460mg once every 3 weeks (q3w), 465mg once every 3 weeks (q3w), 470 mg once every 3 weeks (q3w), 475 mg once every 3 weeks (q3w), 480 mg once every 3 weeks (q3w), 485 mg once every 3 weeks (q3w), 490 mg once every 3 weeks (q3w), 495 mg once every 3 weeks (q3w), 500 mg once every 3 weeks (q3w), 505 mg once every 3 weeks (q3w), 510 mg once every 3 weeks (q3w), 515 mg once every 3 weeks (q3w), 520 mg once every 3 weeks (q3w), 525 mg once every 3 weeks (q3w), 530 mg once every 3 weeks (q3w), 535 mg once every 3 weeks (q3w), 540 mg once every 3 weeks (q3w), 545 mg once every 3 weeks once (q3w), 550mg once every 3 weeks (q3w), 555mg once every 3 weeks (q3w), 560mg once every 3 weeks (q3w), 565mg once every 3 weeks (q3w), 570mg once every 3 weeks (q3w), 575mg once every 3 weeks (q3w), 580mg once every 3 weeks (q3w), 585mg once every 3 weeks (q3w), 590mg once every 3 weeks (q3w), 595mg once every 3 weeks (q3w), 600mg once every 3 weeks (q3w), 605mg once every 3 weeks (q3w), 610mg once every 3 weeks (q3w), 615mg once every 3 weeks (q3w), 620mg once every 3 weeks (q3w),625 mg once every 3 weeks (q3w), 630 mg once every 3 weeks (q3w), 635 mg once every 3 weeks (q3w), 640 mg once every 3 weeks (q3w), 645 mg once every 3 weeks (q3w), 650 mg once every 3 weeks (q3w), 655 mg once every 3 weeks (q3w), 660 mg once every 3 weeks (q3w), 665 mg once every 3 weeks (q3w), 670 mg once every 3 weeks (q3w), 675 mg once every 3 weeks (q3w), 680 mg once every 3 weeks (q3w), 685 mg once every 3 weeks (q3w), 690 mg once every 3 weeks (q3w), 695 mg once every 3 weeks (q3w), 700 mg every 3 weeks once (q3w), 705mg once every 3 weeks (q3w), 710mg once every 3 weeks (q3w), 715mg once every 3 weeks (q3w), 720mg once every 3 weeks (q3w), 725mg once every 3 weeks (q3w), 730mg once every 3 weeks (q3w), 735mg once every 3 weeks (q3w), 740mg once every 3 weeks (q3w), 745mg once every 3 weeks (q3w), 750mg once every 3 weeks (q3w), 755mg once every 3 weeks (q3w), 760mg once every 3 weeks (q3w), 765mg once every 3 weeks (q3w), 770mg once every 3 weeks (q3w), 775mg once every 3 weeks (q3w), 780 mg once every 3 weeks (q3w), 785 mg once every 3 weeks (q3w), 790 mg once every 3 weeks (q3w), 795 mg once every 3 weeks (q3w), 800 mg once every 3 weeks (q3w), 805 mg once every 3 weeks (q3w), 810 mg once every 3 weeks (q3w), 815 mg once every 3 weeks (q3w), 820 mg once every 3 weeks (q3w), 825 mg once every 3 weeks (q3w), 830 mg once every 3 weeks (q3w), 835 mg once every 3 weeks (q3w), 840 mg once every 3 weeks (q3w), 845 mg once every 3 weeks (q3w), 850 mg once every 3 weeks (q3w), 855 mg once every 3 weeks once (q3w), 860mg once every 3 weeks (q3w), 865mg once every 3 weeks (q3w), 870mg once every 3 weeks (q3w), 875mg once every 3 weeks (q3w), 880mg once every 3 weeks (q3w), 885mg once every 3 weeks (q3w), 890mg once every 3 weeks (q3w), 895mg once every 3 weeks (q3w), 900mg once every 3 weeks (q3w), 905mg once every 3 weeks (q3w), 910mg once every 3 weeks (q3w), 915mg once every 3 weeks (q3w), 920mg once every 3 weeks (q3w), 925mg once every 3 weeks (q3w), 930mg once every 3 weeks (q3w),935 mg once every 3 weeks (q3w), 940 mg once every 3 weeks (q3w), 945 mg once every 3 weeks (q3w), 950 mg once every 3 weeks (q3w), 955 mg once every 3 weeks (q3w), 960 mg once every 3 weeks (q3w), 965 mg once every 3 weeks (q3w), 970 mg once every 3 weeks (q3w), 975 mg once every 3 weeks (q3w), 980 mg once every 3 weeks (q3w), 985 mg once every 3 weeks (q3w), 990 mg once every 3 weeks (q3w), 995 mg once every 3 weeks (q3w), 1000 mg once every 3 weeks (q3w). And in some embodiments, a single bolus can be administered, and in some embodiments, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the circumstances. ,

[0579] In addition, although the subject of the methods and uses is generally a cancer patient, the age of the patient is not limited. The disclosed methods and uses can be used to treat cancers, malignant diseases or cancer cell proliferations with various recurrences and prognostic results throughout all age groups and cohorts. Therefore, in some embodiments, the subject may be a pediatric subject, while in other embodiments, the subject may be an adult subject.

[0580] In some embodiments, the objective remission rate of the subject of the ADC of the present disclosure is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70% or about 80%. In a preferred embodiment, the objective remission rate of the subject of the ADC of the present disclosure is at least about 20%. In a further preferred embodiment, the objective remission rate of the subject of the ADC of the present disclosure is at least about 30%. In a further preferred embodiment, the objective remission rate of the subject of the ADC of the present disclosure is at least about 40%. In a further preferred embodiment, the objective remission rate of the subject of the ADC of the present disclosure is at least about 50%. In a further preferred embodiment, the objective remission rate of the subject of the ADC of the present disclosure is at least about 60%. In a further preferred embodiment, the objective remission rate of the subject of the ADC of the present disclosure is at least about 70%. In a further preferred embodiment, the objective remission rate of the subject of the ADC of the present disclosure is at least about 80%.

[0581] In some embodiments, the progression-free survival of a subject administered an ADC of the present disclosure is at least 3.0, 3.5, 4.0, 4.5, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.5, 15.0 months. In a preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 4.0 months. In a further preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 4.5 months. In a further preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 5.0 months. In a further preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 5.5 months. In a further preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 6.0 months. In a further preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 6.5 months. In a further preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 7.0 months. In a further preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 7.5 months. In a further preferred embodiment, the progression-free survival of the subject administered with the ADC of the present disclosure is at least 8.0 months. In a further preferred embodiment, the progression-free survival of a subject administered an ADC of the present disclosure is at least 8.5 months. In a further preferred embodiment, the progression-free survival of a subject administered an ADC of the present disclosure is at least 9.0 months. In a further preferred embodiment, the progression-free survival of a subject administered an ADC of the present disclosure is at least 9.5 months.In further preferred embodiments, the progression-free survival of a subject administered an ADC of the present disclosure is at least 10.0 months. In further preferred embodiments, the progression-free survival of a subject administered an ADC of the present disclosure is at least 5.6, 5.8, 7.9 or 13.9 months.

[0582] In some embodiments, the median progression-free survival of subjects administered an ADC of the present disclosure is at least 3.0, 3.5, 4.0, 4.5, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.5, 15.0 months. In preferred embodiments, the median progression-free survival of the subject administered with the ADC of the present disclosure is at least 4.0 months. In further preferred embodiments, the median progression-free survival of the subject administered with the ADC...

Claims

1. An anti-CDH6 antibody-drug conjugate for treating or preventing cancer, the antibody-drug conjugate comprising an anti-CDH6 antibody and an anti-tumor compound connected by a linker, wherein the linker and the anti-tumor compound are represented by the following formula: -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) Wherein -(succinimide-3-yl-N)- has a structure represented by the following formula: It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: The nitrogen atom of the amino group at position 1 is a connection position, wherein the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

2. The antibody-drug conjugate of claim 1, wherein the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

63.

3. The antibody-drug conjugate according to claim 1 or 2, which has a structure represented by the following formula: wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

4. The antibody-drug conjugate according to any one of claims 1 to 3, wherein the antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 in SEQ ID NO: 69 and a light chain comprising the amino acid sequence of positions 21 to 233 in SEQ ID NO:

61.

5. The antibody-drug conjugate according to any one of claims 1 to 4, wherein the heavy chain or light chain has undergone one or two or more modifications selected from the following: N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of N-terminal glutamine or N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus. 6 . The antibody-drug conjugate of any one of claims 1 to 5 , wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

7. The antibody-drug conjugate according to any one of claims 1 to 6, wherein the average number of units of the anti-tumor compound conjugated per antibody is in the range of 2 to 8.

8. The antibody-drug conjugate according to any one of claims 1 to 7, wherein the average number of units of the anti-tumor compound conjugated per antibody is 7 to 8.

9. The antibody-drug conjugate according to any one of claims 1 to 8, wherein a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

10. The antibody-drug conjugate according to any one of claims 1 to 8, wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

11. The antibody-drug conjugate according to any one of claims 1 to 8, wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 9.6 mg / kg is administered to a subject suffering from cancer.

12. The antibody-drug conjugate according to any one of claims 1 to 8, wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 8.0 mg / kg is administered to a subject suffering from cancer.

13. The antibody-drug conjugate according to any one of claims 1 to 8, wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 6.4 mg / kg is administered to a subject suffering from cancer.

14. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 8.0 mg / kg is administered to a subject suffering from cancer.

15. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 6.4 mg / kg is administered to a subject suffering from cancer.

16. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, or about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

17. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

18. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

19. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of about 5.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

20. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of about 5.6 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

21. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

22. The antibody-drug conjugate of any one of claims 1 to 8, wherein a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject suffering from cancer.

23. The antibody-drug conjugate of any one of claims 1 to 8, wherein 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.10 mg / kg, 7.11 mg / kg, 7.12 mg / kg, 7.13 mg / kg, 7.14 mg / kg, 7.15 mg / kg, 7.16 mg / kg, 7.17 mg / kg, 7.18 mg / kg, 7.19 mg / kg, 7.20 mg / kg, 7.21 mg / kg, 7.22 mg / kg, 7.23 mg / kg or 6.4 mg / kg of the antibody-drug conjugate.

24. The antibody-drug conjugate of any one of claims 1 to 23, wherein the antibody-drug conjugate is administered by intravenous administration.

25. The antibody-drug conjugate of any one of claims 1 to 24, wherein the antibody-drug conjugate is administered once every 3 weeks.

26. The antibody-drug conjugate of any one of claims 1 to 25, wherein the cancer is selected from renal cell carcinoma, clear cell renal carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, clear cell carcinoma of the ovary, endometrioid carcinoma of the ovary, ovarian mucinous tumors, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, nasopharyngeal carcinoma, prostate cancer, or a cancer associated with von Schilling-Lin disease.

27. The antibody-drug conjugate of claim 26, wherein the cancer is renal cell carcinoma, clear cell renal carcinoma, or papillary renal cell carcinoma.

28. The antibody-drug conjugate of claim 26, wherein the cancer is ovarian cancer.

29. The antibody-drug conjugate of claim 28, wherein the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

30. The antibody-drug conjugate of any one of claims 1 to 29, wherein the cancer is metastatic.

31. The antibody-drug conjugate of any one of claims 1 to 30, wherein the cancer is resistant or refractory.

32. The antibody-drug conjugate of claim 31, wherein the resistance or refractoriness is resistance or refractoriness acquired by cancer due to treatment with an anticancer drug.

33. The antibody-drug conjugate of claim 32, wherein the anti-cancer drug is a platinum-based chemotherapy drug, a chemotherapy drug, a PARP inhibitor, an immune checkpoint inhibitor, an angiogenesis inhibitor, or a VEGFR-TKI.

34. The antibody-drug conjugate of any one of claims 1 to 33, wherein the subject has a history of treatment with one or two or more anti-cancer drugs selected from platinum-based chemotherapeutics, chemotherapeutics, PARP inhibitors, immune checkpoint inhibitors, angiogenesis inhibitors, and VEGFR-TKIs.

35. The antibody-drug conjugate of claim 32, wherein the anti-cancer drug is a platinum-based chemotherapy drug.

36. The antibody-drug conjugate of claim 35, wherein the platinum-based chemotherapeutic drug comprises a platinum-based drug and a taxane.

37. The antibody-drug conjugate of any one of claims 1 to 36, wherein the cancer is a CDH6-expressing cancer.

38. The antibody-drug conjugate of claim 37, wherein the CDH6-expressing cancer is a CDH6-overexpressing cancer.

39. The antibody-drug conjugate of any one of claims 1 to 38, wherein the cancer is an inoperable or recurrent cancer.

40. The antibody-drug conjugate of any one of claims 1 to 39, wherein the subject exhibited recurrence of cancer prior to administration of the antibody-drug conjugate.

41. The antibody-drug conjugate of claim 40, wherein recurrence of the cancer occurs at or within about six months of completing a chemotherapy regimen comprising a platinum-based drug.

42. The antibody-drug conjugate of claim 40, wherein recurrence of the cancer occurs at or within about six months of completion of a chemotherapy regimen comprising a platinum-based drug and a taxane.

43. The antibody-drug conjugate of claim 40, wherein recurrence of the cancer occurs within or after about six months of completion of a chemotherapy regimen comprising a platinum-based drug.

44. The antibody-drug conjugate of claim 40, wherein recurrence of the cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

45. The antibody-drug conjugate of any one of claims 1 to 44, wherein the subject has an objective response rate of at least about 20%.

46. ​​The antibody-drug conjugate of any one of claims 1 to 44, wherein the subject has an objective response rate of at least about 30%.

47. The antibody-drug conjugate of any one of claims 1 to 46, wherein the progression-free survival of the subject after administration of the antibody-drug conjugate is at least 5 months.

48. The antibody-drug conjugate of any one of claims 1 to 46, wherein the progression-free survival of the subject after administration of the antibody-drug conjugate is at least 5.5 months.

49. The antibody-drug conjugate of any one of claims 1 to 48, wherein the antibody-drug conjugate is administered as a monotherapy.

50. The antibody-drug conjugate of any one of claims 1 to 48, wherein the ADC is administered to a subject together with a second drug.

51. The antibody-drug conjugate of claim 50, wherein the antibody-drug conjugate is administered before, after, or simultaneously with the second drug.

52. The antibody-drug conjugate of any one of claims 1 to 44, wherein the antibody-drug conjugate is administered as maintenance therapy.

53. The antibody-drug conjugate of any one of claims 1 to 44, wherein the antibody-drug conjugate is administered as an adjuvant therapy.

54. The antibody-drug conjugate of any one of claims 1 to 44, wherein the antibody-drug conjugate is administered following surgical resection of the tumor.

55. The antibody-drug conjugate of any one of claims 1 to 44, wherein the antibody-drug conjugate is administered as a tumor adjuvant therapy.

56. The antibody-drug conjugate of any one of claims 1 to 44, wherein the antibody-drug conjugate is administered prior to surgical resection of the tumor.

57. An anti-CDH6 antibody-drug conjugate for use in treating or preventing cancer, wherein the anti-CDH6 antibody-drug conjugate has a structure represented by the following formula: wherein AB represents an anti-CDH6 antibody or a functional fragment of the antibody, n represents the average number of units of a drug-linker structure conjugated to the antibody per antibody, and the antibody is connected to the linker via a thiol group derived from the antibody; and wherein the anti-CDH6 antibody-drug conjugate is a salt thereof or a hydrate of the anti-CDH6 antibody-drug conjugate or the salt, wherein the average number of units of the drug-linker structure conjugated to each antibody is 7 to 8, wherein the antibody comprises: a heavy chain amino acid sequence shown in SEQ ID NO: 87 or an amino acid sequence derived from the amino acid sequence shown in SEQ ID NO: 87 in which one or two amino acids are deleted from its carboxyl terminus; and a light chain amino acid sequence shown in SEQ ID NO: 88, wherein the dosage of the antibody-drug conjugate is in the range of 1.6 mg / kg to 9.6 mg / kg, wherein the antibody-drug conjugate is administered by intravenous administration, wherein the antibody-drug conjugate is administered once every 3 weeks.

58. A pharmaceutical composition comprising the antibody-drug conjugate or a salt thereof according to any one of claims 1 to 57 as an active ingredient, and a pharmaceutically acceptable formulation component.

59. A method for treating or preventing cancer in a subject, comprising administering to a subject having cancer an anti-CDH6 antibody-drug conjugate, the anti-CDH6 antibody-drug conjugate comprising an anti-CDH6 antibody and an anti-tumor compound connected by a linker, wherein the linker and the anti-tumor compound are represented by the following formula: -(Succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX) Wherein -(succinimide-3-yl-N)- has a structure represented by the following formula: It is linked to the antibody at position 3 thereof, and is linked to a methylene group in a linker structure comprising the structure at a nitrogen atom at position 1, and (NH-DX) represents a group represented by the following formula: The nitrogen atom of the amino group at position 1 is a connection position, wherein the anti-CDH6 antibody comprises CDRH1 consisting of the amino acid sequence of SEQ ID NO: 17, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 60, and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 19 in its heavy chain variable region, and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 12, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 13, and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 14 in its light chain variable region.

60. The method of claim 59, wherein the antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:71 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

63.

61. The method of claim 59 or 60, wherein the antibody-drug conjugate has a structure represented by the following formula: wherein Ab is an antibody comprising a heavy chain variable region comprising SEQ ID NO: 71 and a light chain variable region comprising SEQ ID NO: 63, and n represents the average number of units of a drug-linker structure conjugated to said antibody per antibody, wherein the average number of units of the selected drug-linker structure conjugated to each antibody is in the range of 1 to 10.

62. The method of any one of claims 59 to 61, wherein the antibody comprises: a heavy chain comprising the amino acid sequence of positions 20 to 471 in SEQ ID NO:69 and a light chain comprising the amino acid sequence of positions 21 to 233 in SEQ ID NO:

61.

63. The method of any one of claims 59 to 62, wherein the heavy chain or light chain has undergone one or two or more modifications selected from the group consisting of N-linked glycosylation, O-linked glycosylation, N-terminal processing, C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, addition of a methionine residue to the N-terminus, amidation of a proline residue, conversion of an N-terminal glutamine or an N-terminal glutamate to pyroglutamate, and deletion of one or two amino acids from the carboxyl terminus.

64. The method of any one of claims 59 to 63, wherein the anti-CDH6 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.

65. The method of any one of claims 59 to 64, wherein the average number of units of anti-tumor compound conjugated per antibody is in the range of 2 to 8.

66. The method according to any one of claims 59 to 65, wherein the average number of units of anti-tumor compound conjugated per antibody is 7 to 8.

67. The method of any one of claims 59 to 66, wherein a dose of the antibody-drug conjugate in the range of 1.6 mg / kg to 9.6 mg / kg is administered to a subject having cancer.

68. The method of any one of claims 59 to 66, wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 9.6 mg / kg is administered to a subject having cancer.

69. The method of any one of claims 59 to 66, wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 9.6 mg / kg is administered to a subject having cancer.

70. The method of any one of claims 59 to 66, wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 8.0 mg / kg is administered to a subject having cancer.

71. The method of any one of claims 59 to 66, wherein a dose of the antibody-drug conjugate in the range of 3.2 mg / kg to 6.4 mg / kg is administered to a subject having cancer.

72. The method of any one of claims 59 to 66, wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 8.0 mg / kg is administered to a subject having cancer.

73. The method of any one of claims 59 to 66, wherein a dose of the antibody-drug conjugate in the range of 4.8 mg / kg to 6.4 mg / kg is administered to a subject having cancer.

74. The method of any one of claims 59 to 66, wherein a dose of about 3.2 mg / kg, about 4.8 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 6.4 mg / kg, or about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject having cancer.

75. The method of any one of claims 59 to 66, wherein a dose of about 3.2 mg / kg of the antibody-drug conjugate is administered to a subject having cancer.

76. The method of any one of claims 59 to 66, wherein a dose of about 4.8 mg / kg of the antibody-drug conjugate is administered to a subject having cancer.

77. The method of any one of claims 59 to 66, wherein a dose of about 5.4 mg / kg of the antibody-drug conjugate is administered to a subject having cancer.

78. The method of any one of claims 59 to 66, wherein a dose of about 5.6 mg / kg of the antibody-drug conjugate is administered to a subject having cancer.

79. The method of any one of claims 59 to 66, wherein a dose of about 6.4 mg / kg of the antibody-drug conjugate is administered to a subject having cancer.

80. The method of any one of claims 59 to 66, wherein a dose of about 8.0 mg / kg of the antibody-drug conjugate is administered to a subject having cancer.

81. The method of any one of claims 59 to 66, wherein 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7.10 mg / kg, 7. or 6.4 mg / kg of the antibody-drug conjugate.

82. The method of any one of claims 59 to 81, wherein the antibody-drug conjugate is administered by intravenous administration.

83. The method of any one of claims 59 to 82, wherein the antibody-drug conjugate is administered once every 3 weeks.

84. The method of any one of claims 59 to 83, wherein the cancer is selected from renal cell carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma, ovarian cancer, ovarian serous adenocarcinoma, clear cell carcinoma of the ovary, endometrioid carcinoma of the ovary, ovarian mucinous tumors, thyroid cancer, bile duct cancer, lung cancer, non-small cell lung cancer, cervical cancer, brain tumor, head and neck cancer, sarcoma, osteosarcoma, small cell lung cancer, glioblastoma, mesothelioma, uterine cancer, pancreatic cancer, Wilms' tumor, neuroblastoma, colorectal cancer, gastric cancer, endometrial cancer, nasopharyngeal carcinoma, prostate cancer, or a cancer associated with von Schiele-Lin disease.

85. The method of claim 84, wherein the cancer is renal cell carcinoma, clear cell renal carcinoma, or papillary renal cell carcinoma.

86. The method of claim 84, wherein the cancer is ovarian cancer.

87. The method of claim 86, wherein the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

88. The antibody-drug conjugate of any one of claims 59 to 87, wherein the cancer is metastatic.

89. The method of any one of claims 59 to 88, wherein the cancer is resistant or refractory.

90. The method of claim 89, wherein the resistance or refractoriness is resistance or refractoriness acquired by the cancer as a result of treatment with an anticancer drug.

91. The method of claim 90, wherein the anticancer drug is a platinum-based chemotherapy drug, a chemotherapy drug, a PARP inhibitor, an immune checkpoint inhibitor, an angiogenesis inhibitor, or a VEGFR-TKI.

92. The method of any one of claims 59 to 91, wherein the subject has a history of treatment with one or two or more anti-cancer drugs selected from platinum-based chemotherapy drugs, chemotherapeutic drugs, PARP inhibitors, immune checkpoint inhibitors, angiogenesis inhibitors, and VEGFR-TKIs.

93. The method of claim 90, wherein the anti-cancer drug is a platinum-based chemotherapy drug.

94. The method of claim 93, wherein the platinum-based chemotherapy drug comprises a platinum-based drug and a taxane.

95. The method of any one of claims 59 to 94, wherein the cancer is a cancer that expresses CDH6.

96. The method of claim 95, wherein the CDH6-expressing cancer is a CDH6-overexpressing cancer.

97. The method of any one of claims 59 to 96, wherein the cancer is an inoperable or recurrent cancer.

98. The method of any one of claims 59 to 97, wherein the subject exhibited recurrence of cancer prior to administration of the antibody-drug conjugate.

99. The method of claim 98, wherein recurrence of the cancer occurs at or within about six months of completing a chemotherapy regimen comprising a platinum-based drug.

100. The method of claim 98, wherein recurrence of the cancer occurs at or within about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

101. The method of claim 98, wherein recurrence of the cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug.

102. The method of claim 98, wherein recurrence of the cancer occurs within or after about six months of completing a chemotherapy regimen comprising a platinum-based drug and a taxane.

103. The method of any one of claims 59 to 102, wherein the subject has an objective response rate of at least about 20%.

104. The method of any one of claims 59 to 102, wherein the subject has an objective response rate of at least about 30%.

105. The method of any one of claims 59 to 104, wherein the subject's progression-free survival is at least 5 months following administration of the antibody-drug conjugate.

106. The method of any one of claims 59 to 104, wherein the subject's progression-free survival after administration of the antibody-drug conjugate is at least 5.5 months.

107. The method of any one of claims 59 to 106, wherein the antibody-drug conjugate is administered as a monotherapy.

108. The method of any one of claims 59 to 106, wherein the ADC is administered to the subject together with a second drug.

109. The method of claim 108, wherein the antibody-drug conjugate is administered before, after, or simultaneously with the second drug.

110. The method of any one of claims 59 to 102, wherein the antibody-drug conjugate is administered as maintenance therapy.

111. The method of any one of claims 59 to 102, wherein the antibody-drug conjugate is administered as adjuvant therapy.

112. The method of any one of claims 59 to 102, wherein the antibody-drug conjugate is administered following surgical resection of the tumor.

113. The method of any one of claims 59 to 102, wherein the antibody-drug conjugate is administered as an adjuvant tumor therapy.

114. The method of any one of claims 59 to 102, wherein the antibody-drug conjugate is administered prior to surgical resection of the tumor.

115. A method of treating or preventing cancer in a subject, comprising administering to a subject having cancer an anti-CDH6 antibody-drug conjugate having a structure represented by the following formula: wherein AB represents an anti-CDH6 antibody or a functional fragment of the antibody, n represents the average number of units of a drug-linker structure conjugated to the antibody per antibody, and the antibody is connected to the linker via a thiol group derived from the antibody; and wherein the anti-CDH6 antibody-drug conjugate is a salt thereof or a hydrate of the anti-CDH6 antibody-drug conjugate or the salt, wherein the average number of units of the drug-linker structure conjugated to each antibody is 7 to 8, wherein the antibody comprises: a heavy chain amino acid sequence shown in SEQ ID NO: 87 or an amino acid sequence derived from the amino acid sequence shown in SEQ ID NO: 87 in which one or two amino acids are deleted from its carboxyl terminus; and a light chain amino acid sequence shown in SEQ ID NO: 88, wherein the dosage of the antibody-drug conjugate is in the range of 1.6 mg / kg to 9.6 mg / kg, wherein the antibody-drug conjugate is administered by intravenous administration, wherein the antibody-drug conjugate is administered once every 3 weeks.

116. The method of any one of claims 59 to 115, wherein the antibody-drug conjugate is administered in a pharmaceutical composition comprising at least one pharmaceutically acceptable formulation component.

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